rs3087523

chr2-105361319-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001318895.3(FHL2):c.804C>T(p.Asp268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,654 control chromosomes in the GnomAD database, including 10,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (710 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9657 hom.)
• Consequence: FHL2 NM_001318895.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.653

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]

C2orf49 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-105361319-G-A is Benign according to our data. Variant chr2-105361319-G-A is described in ClinVar as [Benign]. Clinvar id is 48331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105361319-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.653 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL2	NM_001318895.3	c.804C>T	p.Asp268=	synonymous_variant	7/7	ENST00000530340.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL2	ENST00000530340.6	c.804C>T	p.Asp268=	synonymous_variant	7/7	1	NM_001318895.3	P1

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13176 AN: 152116 Hom.: 710 Cov.: 32

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.0939

GnomAD3 exomes AF: 0.0936 AC: 23481 AN: 250918 Hom.: 1246 AF XY: 0.0934 AC XY: 12675 AN XY: 135668

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.0901

Gnomad EAS exome AF: 0.0253

Gnomad SAS exome AF: 0.0552

Gnomad FIN exome AF: 0.0975

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.111 AC: 161934 AN: 1461420 Hom.: 9657 Cov.: 32 AF XY: 0.109 AC XY: 79500 AN XY: 727036

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.0896

Gnomad4 EAS exome AF: 0.0207

Gnomad4 SAS exome AF: 0.0548

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0866 AC: 13179 AN: 152234 Hom.: 710 Cov.: 32 AF XY: 0.0849 AC XY: 6318 AN XY: 74432

Gnomad4 AFR AF: 0.0257

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0927

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.0995

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.0929

Alfa AF: 0.111 Hom.: 1286

Bravo AF: 0.0849

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 16, 2012	Asp268Asp in exon 6 of FHL2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 12% (868/7020) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs3087523). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2018

- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.21
Dann	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs3087523; hg19: chr2-105977776; COSMIC: COSV59079045; COSMIC: COSV59079045;