11-19182496-A-C

Variant names:

• chr11-19182496-A-C
• rs45597034
• NM_003476.5:c.*174T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003476.5(CSRP3):​c.*174T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000602 in 664,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: CSRP3 NM_003476.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: SD, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• hypertrophic cardiomyopathy 12

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1M

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003476.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRP3	NM_003476.5	MANE Select	c.*174T>G		3_prime_UTR	Exon 6 of 6	NP_003467.1	A2TDB8
	CSRP3	NM_001369404.1		c.*137T>G		3_prime_UTR	Exon 5 of 5	NP_001356333.1	A0A3B3ISZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRP3	ENST00000265968.9	TSL:1 MANE Select	c.*174T>G		3_prime_UTR	Exon 6 of 6	ENSP00000265968.3	P50461-1
	CSRP3	ENST00000533783.2	TSL:1	c.*174T>G		3_prime_UTR	Exon 7 of 7	ENSP00000431813.1	P50461-1
	CSRP3	ENST00000951070.1		c.*174T>G		3_prime_UTR	Exon 6 of 6	ENSP00000621129.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000390 AC: 2 AN: 512728 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 274724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13688

American (AMR) AF: 0.00 AC: 0 AN: 25622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16954

East Asian (EAS) AF: 0.0000311 AC: 1 AN: 32144

South Asian (SAS) AF: 0.0000184 AC: 1 AN: 54446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 298174

Other (OTH) AF: 0.00 AC: 0 AN: 28478

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.11

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

Other links and lift over

dbSNP: rs45597034; hg19: chr11-19204043;