chr11-19186294-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

6

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
CSRP3NM_003476.5 linkc.336G>A p.Ala112Ala synonymous_variant Exon 4 of 6 ENST00000265968.9 NP_003467.1 P50461-1A2TDB8
CSRP3NM_001369404.1 linkc.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
CSRP3ENST00000265968.9 linkc.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.:
32
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.:
33
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.:
32
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:
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:1Uncertain:1Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
Feb 15, 2008
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
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

- -

-
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

- -

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

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:2
Nov 19, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
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. -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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