rs45476991

Positions:

chr11-19188204-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The ENST00000265968.9(CSRP3):c.213C>T(p.Ile71=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,613,806 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 70 hom. )

Consequence

CSRP3
ENST00000265968.9 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.302

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 11-19188204-G-A is Benign according to our data. Variant chr11-19188204-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-19188204-G-A is described in Lovd as [Benign]. Variant chr11-19188204-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.302 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00489 (744/152264) while in subpopulation NFE AF= 0.00769 (523/68016). AF 95% confidence interval is 0.00714. There are 1 homozygotes in gnomad4. There are 324 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 70 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSRP3	NM_003476.5 linkuse as main transcript	c.213C>T	p.Ile71=	synonymous_variant	3/6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1 linkuse as main transcript	c.113-1856C>T		intron_variant			NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9 linkuse as main transcript	c.213C>T	p.Ile71=	synonymous_variant	3/6	1	NM_003476.5	ENSP00000265968	P1	P50461-1

Frequencies

GnomAD3 genomes

AF:

0.00489

AC:

744

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00769

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00505

AC:

1268

AN:

251298

Hom.:

AF XY:

0.00498

AC XY:

677

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.00743

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00787

AC:

11498

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

5501

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00390

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00321

Gnomad4 FIN exome

AF:

0.00653

Gnomad4 NFE exome

AF:

0.00917

Gnomad4 OTH exome

AF:

0.00774

GnomAD4 genome

AF:

0.00489

AC:

744

AN:

152264

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

324

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00603

Gnomad4 NFE

AF:

0.00769

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.00465

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00840

EpiControl

AF:

0.00693

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 11, 2010	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2013	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. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CSRP3: BP4, BP7, BS2 -

Hypertrophic cardiomyopathy 12

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 28, 2018

- -

Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2015

This alteration is classified as likely 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

-0.37

CADD

Benign

8.8

DANN

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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