rs3792269

chr2-240592062-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_023083.4(CAPN10):c.600A>G(p.Pro200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,608,754 control chromosomes in the GnomAD database, including 21,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1450 hom., cov: 34)
  • Exomes 𝑓: 0.16 (19908 hom.)
• Consequence: CAPN10 NM_023083.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53

Genes affected

CAPN10 (HGNC:1477): (calpain 10) Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region. Multiple alternative transcript variants have been described for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-240592062-A-G is Benign according to our data. Variant chr2-240592062-A-G is described in ClinVar as [Benign]. Clinvar id is 3056633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN10	NM_023083.4	c.600A>G	p.Pro200=	synonymous_variant	4/12	ENST00000391984.7
CAPN10	NM_023085.4	c.600A>G	p.Pro200=	synonymous_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN10	ENST00000391984.7	c.600A>G	p.Pro200=	synonymous_variant	4/12	1	NM_023083.4	P1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19133 AN: 152170 Hom.: 1449 Cov.: 34

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.0983

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.147 AC: 34872 AN: 237336 Hom.: 2848 AF XY: 0.153 AC XY: 19685 AN XY: 128790

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.0834

Gnomad ASJ exome AF: 0.0904

Gnomad EAS exome AF: 0.0986

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.162 AC: 235490 AN: 1456466 Hom.: 19908 Cov.: 33 AF XY: 0.162 AC XY: 117566 AN XY: 724172

Gnomad4 AFR exome AF: 0.0416

Gnomad4 AMR exome AF: 0.0839

Gnomad4 ASJ exome AF: 0.0898

Gnomad4 EAS exome AF: 0.0909

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.126 AC: 19143 AN: 152288 Hom.: 1450 Cov.: 34 AF XY: 0.127 AC XY: 9449 AN XY: 74462

Gnomad4 AFR AF: 0.0470

Gnomad4 AMR AF: 0.0992

Gnomad4 ASJ AF: 0.0835

Gnomad4 EAS AF: 0.0986

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.118

Alfa AF: 0.152 Hom.: 2439

Bravo AF: 0.114

Asia WGS AF: 0.147 AC: 512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CAPN10-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.28
Dann	Benign	0.23

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: rs3792269; hg19: chr2-241531479; COSMIC: COSV54376677; COSMIC: COSV54376677;