rs45552933

Positions:

• chr11-19188203-C-A
• chr11-19188203-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003476.5(CSRP3):​c.214G>T​(p.Gly72Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G72G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSRP3	NM_003476.5	c.214G>T	p.Gly72Trp	missense_variant	3/6	ENST00000265968.9	NP_003467.1
CSRP3	NM_001369404.1	c.113-1855G>T		intron_variant			NP_001356333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSRP3	ENST00000265968.9	c.214G>T	p.Gly72Trp	missense_variant	3/6	1	NM_003476.5	ENSP00000265968.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	M;.;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.6	D;.;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;.;D;D
Vest4		0.73
MutPred		0.58		Loss of disorder (P = 0.0263);Loss of disorder (P = 0.0263);Loss of disorder (P = 0.0263);Loss of disorder (P = 0.0263);
MVP		0.96
MPC		0.41
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.69

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: rs45552933; hg19: chr11-19209750;