NM_001318895.3:c.85G>A

Variant names:

• chr2-105386432-C-T
• rs56284940
• NM_001318895.3:c.85G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001318895.3(FHL2):​c.85G>A​(p.Val29Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,228 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V29A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00099 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.21
• Publications: 3 publications found

Genes affected

FHL2 (HGNC:3703): (four and a half LIM domains 2) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2016]

FHL2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054731518).
• BP6: Variant 2-105386432-C-T is Benign according to our data. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386432-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 48333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL2	NM_001318895.3	c.85G>A	p.Val29Met	missense_variant	Exon 3 of 7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6	c.85G>A	p.Val29Met	missense_variant	Exon 3 of 7	1	NM_001318895.3	ENSP00000433567.2

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00109 AC: 274 AN: 251470 AF XY: 0.00129

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00154 AC: 2250 AN: 1461890 Hom.: 5 Cov.: 31 AF XY: 0.00167 AC XY: 1213 AN XY: 727246

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00257 AC: 222 AN: 86256

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00167 AC: 1855 AN: 1112012

Other (OTH) AF: 0.00147 AC: 89 AN: 60396

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74494

African (AFR) AF: 0.000385 AC: 16 AN: 41578

American (AMR) AF: 0.000522 AC: 8 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68038

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.000926

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 06, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Benign:1

Feb 12, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FHL2-related disorder Benign:1

Jun 29, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;T;T;T;.;T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;D;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.055	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	.;.;M;M;M;M;M;M;.
PhyloP100		2.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	.;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.010	.;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D;T
Polyphen		0.88	.;.;P;P;P;.;P;P;.
Vest4		0.59
MVP		0.96
MPC		0.35
ClinPred		0.044	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56284940; hg19: chr2-106002889;