rs45582433

Variant names:

• chr11-19186318-G-C
• rs45582433
• NM_003476.5:c.312C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369404.1(CSRP3):​c.143C>G​(p.Pro48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,614,196 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P48T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (59 hom.)
• Consequence: CSRP3 NM_001369404.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.54
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029513538).
• BP6: Variant 11-19186318-G-C is Benign according to our data. Variant chr11-19186318-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369404.1. 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.312C>G	p.Thr104Thr	synonymous	Exon 4 of 6	NP_003467.1	A2TDB8
	CSRP3	NM_001369404.1		c.143C>G	p.Pro48Arg	missense	Exon 3 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.312C>G	p.Thr104Thr	synonymous	Exon 4 of 6	ENSP00000265968.3	P50461-1
	CSRP3	ENST00000533783.2	TSL:1	c.312C>G	p.Thr104Thr	synonymous	Exon 5 of 7	ENSP00000431813.1	P50461-1
	CSRP3	ENST00000649842.1		c.143C>G	p.Pro48Arg	missense	Exon 3 of 5	ENSP00000497531.1	A0A3B3ISZ2

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2404 AN: 152190 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00374 AC: 939 AN: 251366 AF XY: 0.00253

Gnomad AFR exome AF: 0.0517

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00169 AC: 2470 AN: 1461888 Hom.: 59 Cov.: 32 AF XY: 0.00143 AC XY: 1040 AN XY: 727248

African (AFR) AF: 0.0571 AC: 1913 AN: 33476

American (AMR) AF: 0.00264 AC: 118 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000165 AC: 184 AN: 1112010

Other (OTH) AF: 0.00374 AC: 226 AN: 60396

GnomAD4 genome AF: 0.0158 AC: 2406 AN: 152308 Hom.: 64 Cov.: 32 AF XY: 0.0151 AC XY: 1123 AN XY: 74472

African (AFR) AF: 0.0547 AC: 2273 AN: 41562

American (AMR) AF: 0.00562 AC: 86 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00530 Hom.: 7

Bravo AF: 0.0178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0584 AC: 257

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00474 AC: 575

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	CSRP3-related disorder (1)
-	-	1	Hypertrophic cardiomyopathy 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.0
DANN	Benign	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0030	T
PhyloP100		1.5
GERP RS		2.9
Mutation Taster		=100/0	polymorphism

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: rs45582433; hg19: chr11-19207865;