rs138218523

chr11-19186331-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003476.5(CSRP3):c.299G>A(p.Arg100His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,614,156 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (3 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 2.76

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010199755).
• BP6: Variant 11-19186331-C-T is Benign according to our data. Variant chr11-19186331-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44694.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=7, Uncertain_significance=2}. Variant chr11-19186331-C-T is described in Lovd as [Benign]. Variant chr11-19186331-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000906 (138/152274) while in subpopulation NFE AF= 0.00122 (83/68024). AF 95% confidence interval is 0.00101. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5	c.299G>A	p.Arg100His	missense_variant	4/6	ENST00000265968.9
CSRP3	NM_001369404.1	c.130G>A	p.Ala44Thr	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9	c.299G>A	p.Arg100His	missense_variant	4/6	1	NM_003476.5	P1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00117 AC: 294 AN: 251360 Hom.: 1 AF XY: 0.00116 AC XY: 157 AN XY: 135854

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00504

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000755 AC: 1103 AN: 1461882 Hom.: 3 Cov.: 32 AF XY: 0.000755 AC XY: 549 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00464

Gnomad4 NFE exome AF: 0.000702

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74448

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000917 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.00143 AC: 174

EpiCase AF: 0.000273

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24082139, 19035361, 23861362, 30012424) -

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2012	Variant classified as Uncertain Significance - Favor Benign. The Arg100His varia nt (CSRP3) has been reported in 1 individual with HCM (Anderson 2009) and has be en detected in 1 individual with HCM tested by our laboratory who carried a path ogenic HCM variant (LMM unpublished data). This variant has been identified in 0.1% (6/7020) of European American chromosomes from a broad population by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs13821852 3). While this frequency suggests that it is more likely benign but it is too lo w to confidently rule out a disease causing role. Additional information is need ed to fully assess its clinical significance. -
Benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2021	- -

Hypertrophic cardiomyopathy 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

CSRP3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 04, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2019

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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.010	T
MutationTaster	Benign	1.0	D;D
ClinPred		0.038	T
GERP RS		5.8

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: rs138218523; hg19: chr11-19207878; COSMIC: COSV56390358;