rs113188481

chr2-105363443-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001318895.3(FHL2):c.530G>A(p.Arg177Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,611,134 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R177W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: FHL2 NM_001318895.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.70

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037514567).
• BP6: Variant 2-105363443-C-T is Benign according to our data. Variant chr2-105363443-C-T is described in ClinVar as [Benign]. Clinvar id is 48325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105363443-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2054/152274) while in subpopulation AFR AF= 0.0462 (1921/41546). AF 95% confidence interval is 0.0445. There are 42 homozygotes in gnomad4. There are 977 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2049 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL2	NM_001318895.3	c.530G>A	p.Arg177Gln	missense_variant	6/7	ENST00000530340.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL2	ENST00000530340.6	c.530G>A	p.Arg177Gln	missense_variant	6/7	1	NM_001318895.3	P1
	ENST00000457290.2	n.40+366C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2049 AN: 152156 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00352 AC: 856 AN: 243348 Hom.: 20 AF XY: 0.00254 AC XY: 334 AN XY: 131448

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.00138 AC: 2008 AN: 1458860 Hom.: 45 Cov.: 32 AF XY: 0.00121 AC XY: 876 AN XY: 725396

Gnomad4 AFR exome AF: 0.0484

Gnomad4 AMR exome AF: 0.00314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.0135 AC: 2054 AN: 152274 Hom.: 42 Cov.: 32 AF XY: 0.0131 AC XY: 977 AN XY: 74456

Gnomad4 AFR AF: 0.0462

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00236 Hom.: 18

Bravo AF: 0.0158

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00424 AC: 515

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2012

Arg177Gln in exon 5 of FHL2: This variant is classified as benign based on its h igh frequency in the general population (dbSNP rs113188481). -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 05, 2016

- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.085
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N
PROVEAN	Pathogenic	-5.9	D
Sift	Uncertain	0.0010	D
Vest4		0.32
MVP		0.98
ClinPred		0.024	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs113188481; hg19: chr2-105979900;