rs777883490

chr11-19192409-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_003476.5(CSRP3):c.40G>C(p.Glu14Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CSRP3 NM_003476.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.07

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 3 ACMG points.

• PM1: In a domain LIM zinc-binding 1 (size 51) in uniprot entity CSRP3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_003476.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26587442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSRP3	NM_003476.5	c.40G>C	p.Glu14Gln	missense_variant	2/6	ENST00000265968.9
CSRP3	NM_001369404.1	c.40G>C	p.Glu14Gln	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSRP3	ENST00000265968.9	c.40G>C	p.Glu14Gln	missense_variant	2/6	1	NM_003476.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251462 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 31, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 543037). This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. This variant is present in population databases (rs777883490, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 14 of the CSRP3 protein (p.Glu14Gln). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The p.E14Q variant (also known as c.40G>C), located in coding exon 1 of the CSRP3 gene, results from a G to C substitution at nucleotide position 40. The glutamic acid at codon 14 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.0012	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.30	T;.;.;T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.49	N;.;.;N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.24	N;.;.;.;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.45	T;.;.;.;T;.
Sift4G	Benign	0.54	T;.;.;.;T;.
Polyphen		0.0	B;.;.;B;B;.
Vest4		0.43
MutPred		0.38		Loss of ubiquitination at K9 (P = 0.0453);Loss of ubiquitination at K9 (P = 0.0453);Loss of ubiquitination at K9 (P = 0.0453);Loss of ubiquitination at K9 (P = 0.0453);Loss of ubiquitination at K9 (P = 0.0453);Loss of ubiquitination at K9 (P = 0.0453);
MVP		0.91
MPC		0.098
ClinPred		0.19	T
GERP RS		6.0
Varity_R		0.19
gMVP		0.15

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: rs777883490; hg19: chr11-19213956;