chr11-19186294-C-T

Variant names:

• chr11-19186294-C-T
• rs13451
• NM_003476.5:c.336G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369404.1(CSRP3):​c.167G>A​(p.Arg56Gln) variant causes a missense 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. 7/9 in silico tools predict 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 NM_001369404.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:14
• Conservation: PhyloP100: -1.45

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]

ACMG classification

Verdict is Benign. Variant got -20 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].
• 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 rank	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.336G>A	p.Ala112Ala	synonymous_variant	Exon 4 of 6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.167G>A	p.Arg56Gln	missense_variant	Exon 3 of 5		NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.336G>A	p.Ala112Ala	synonymous_variant	Exon 4 of 6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10946 AN: 152150 Hom.: 543 Cov.: 32

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

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.: 33 AF XY: 0.0953 AC XY: 69293 AN XY: 727232

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.: 32 AF XY: 0.0710 AC XY: 5284 AN XY: 74432

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: 85

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:1 Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Dec 04, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 15, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Primary dilated cardiomyopathy Pathogenic:1

Sep 23, 2014

Cytogenetics- Mohapatra Lab, Banaras Hindu University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Hypertrophic cardiomyopathy 12 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 23, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0019	T
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

Other links and lift over

dbSNP: rs13451; hg19: chr11-19207841; COSMIC: COSV56389467;