11-19186294-C-T

Position:

chr11-19186294-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000265968.9(CSRP3):c.336G>A(p.Ala112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0934 in 1,614,124 control chromosomes in the GnomAD database, including 7,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 545 hom., cov: 32)

Exomes 𝑓: 0.096 ( 7278 hom. )

Consequence

CSRP3
ENST00000265968.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:14

Conservation

PhyloP100: -1.45

Variant links:

Genes affected

CSRP3 (HGNC:2472): (cysteine and glycine rich protein 3) This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

CSRP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018878281).

BP6

Variant 11-19186294-C-T is Benign according to our data. Variant chr11-19186294-C-T is described in ClinVar as [Benign]. Clinvar id is 44696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-19186294-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSRP3	NM_003476.5 linkuse as main transcript	c.336G>A	p.Ala112=	synonymous_variant	4/6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1 linkuse as main transcript	c.167G>A	p.Arg56Gln	missense_variant	3/5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9 linkuse as main transcript	c.336G>A	p.Ala112=	synonymous_variant	4/6	1	NM_003476.5	ENSP00000265968	P1	P50461-1

Frequencies

GnomAD3 genomes

AF:

0.0719

AC:

10946

AN:

152150

Hom.:

543

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0671

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.0572

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0788

GnomAD3 exomes

AF:

0.0798

AC:

20048

AN:

251352

Hom.:

1053

AF XY:

0.0825

AC XY:

11203

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0156

Gnomad AMR exome

AF:

0.0455

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.00261

Gnomad SAS exome

AF:

0.0593

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.0857

GnomAD4 exome

AF:

0.0956

AC:

139749

AN:

1461856

Hom.:

7278

Cov.:

AF XY:

0.0953

AC XY:

69293

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0174

Gnomad4 AMR exome

AF:

0.0473

Gnomad4 ASJ exome

AF:

0.114

Gnomad4 EAS exome

AF:

0.00116

Gnomad4 SAS exome

AF:

0.0579

Gnomad4 FIN exome

AF:

0.105

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.0938

GnomAD4 genome

AF:

0.0719

AC:

10945

AN:

152268

Hom.:

545

Cov.:

AF XY:

0.0710

AC XY:

5284

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0182

Gnomad4 AMR

AF:

0.0670

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.0572

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.104

Gnomad4 OTH

AF:

0.0780

Alfa

AF:

0.0985

Hom.:

1338

Bravo

AF:

0.0670

TwinsUK

AF:

0.105

AC:

389

ALSPAC

AF:

0.108

AC:

415

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.107

AC:

921

ExAC

AF:

0.0819

AC:

9944

Asia WGS

AF:

0.0290

AC:

105

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.111

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 15, 2008	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 11.585% in ExAC) based on the frequency threshold of 5.0% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. 1 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Sep 23, 2014

- -

Hypertrophic cardiomyopathy 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 01, 2019

- -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.39

DANN

Benign

0.73

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0019

MutationTaster

Benign

5.8e-11

P;P

GERP RS

-12

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

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