rs113188481

Positions:

chr2-105363443-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000530340.6(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
ENST00000530340.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.70

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 2054 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL2	NM_001318895.3 linkuse as main transcript	c.530G>A	p.Arg177Gln	missense_variant	6/7	ENST00000530340.6	NP_001305824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL2	ENST00000530340.6 linkuse as main transcript	c.530G>A	p.Arg177Gln	missense_variant	6/7	1	NM_001318895.3	ENSP00000433567	P1	Q14192-1
	ENST00000457290.2 linkuse as main transcript	n.40+366C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2049

AN:

152156

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00254

AC XY:

334

AN XY:

131448

show subpopulations

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.:

Cov.:

AF XY:

0.00121

AC XY:

876

AN XY:

725396

show subpopulations

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.:

Cov.:

AF XY:

0.0131

AC XY:

977

AN XY:

74456

show subpopulations

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.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00424

AC:

515

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

-0.085

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.82

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;N

PROVEAN

Pathogenic

-5.9

Sift

Uncertain

0.0010

Vest4

0.32

MVP

0.98

ClinPred

0.024

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over