chr11-19186294-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003476.5(CSRP3):c.336G>A(p.Ala112Ala) 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
NM_003476.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:15

Conservation

PhyloP100: -1.45

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD, SD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
hypertrophic cardiomyopathy 12
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1M
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CSRP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 44696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CSRP3	NM_003476.5 link	c.336G>A	p.Ala112Ala	synonymous_variant	Exon 4 of 6	ENST00000265968.9	NP_003467.1	P50461-1A2TDB8
CSRP3	NM_001369404.1 link	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 link	c.336G>A	p.Ala112Ala	synonymous_variant	Exon 4 of 6	1	NM_003476.5	ENSP00000265968.3		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

GnomAD2 exomes

AF:

0.0798

AC:

20048

AN:

251352

AF XY:

0.0825

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 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

African (AFR)

AF:

0.0174

AC:

582

AN:

33480

American (AMR)

AF:

0.0473

AC:

2115

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2990

AN:

26136

East Asian (EAS)

AF:

0.00116

AC:

AN:

39700

South Asian (SAS)

AF:

0.0579

AC:

4991

AN:

86258

European-Finnish (FIN)

AF:

0.105

AC:

5588

AN:

53420

Middle Eastern (MID)

AF:

0.0966

AC:

557

AN:

5768

European-Non Finnish (NFE)

AF:

0.105

AC:

117213

AN:

1111976

Other (OTH)

AF:

0.0938

AC:

5667

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7715

15430

23144

30859

38574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4104

8208

12312

16416

20520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0719

AC:

10945

AN:

152268

Hom.:

545

Cov.:

AF XY:

0.0710

AC XY:

5284

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0182

AC:

758

AN:

41564

American (AMR)

AF:

0.0670

AC:

1025

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

389

AN:

3470

East Asian (EAS)

AF:

0.00251

AC:

AN:

5186

South Asian (SAS)

AF:

0.0572

AC:

276

AN:

4824

European-Finnish (FIN)

AF:

0.106

AC:

1119

AN:

10588

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7073

AN:

68024

Other (OTH)

AF:

0.0780

AC:

165

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

518

1036

1554

2072

2590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0960

Hom.:

1575

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Feb 15, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

PreventionGenetics, part of Exact Sciences

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

- -

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.14

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.39

(source)

DANN

Benign

0.73

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0019

PhyloP100

-1.5

GERP RS

-12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over