chr2-240596709-A-G

Position:

• chr2-240596709-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_023083.4(CAPN10):​c.1510A>G​(p.Thr504Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,563,144 control chromosomes in the GnomAD database, including 20,757 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1449 hom., cov: 34)
  • Exomes 𝑓: 0.16 (19308 hom.)
• Consequence: CAPN10 NM_023083.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023303628).
• BP6: Variant 2-240596709-A-G is Benign according to our data. Variant chr2-240596709-A-G is described in ClinVar as [Benign]. Clinvar id is 1296539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN10	NM_023083.4	c.1510A>G	p.Thr504Ala	missense_variant	9/12	ENST00000391984.7
CAPN10	NM_023085.4	c.1279-1179A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN10	ENST00000391984.7	c.1510A>G	p.Thr504Ala	missense_variant	9/12	1	NM_023083.4	P1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19132 AN: 151768 Hom.: 1448 Cov.: 34

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0995

Gnomad ASJ AF: 0.0837

Gnomad EAS AF: 0.0983

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.143 AC: 29630 AN: 206792 Hom.: 2435 AF XY: 0.149 AC XY: 16602 AN XY: 111398

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.0797

Gnomad ASJ exome AF: 0.0887

Gnomad EAS exome AF: 0.0973

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.162 AC: 228210 AN: 1411258 Hom.: 19308 Cov.: 34 AF XY: 0.162 AC XY: 112993 AN XY: 696228

Gnomad4 AFR exome AF: 0.0412

Gnomad4 AMR exome AF: 0.0816

Gnomad4 ASJ exome AF: 0.0901

Gnomad4 EAS exome AF: 0.0916

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.126 AC: 19142 AN: 151886 Hom.: 1449 Cov.: 34 AF XY: 0.127 AC XY: 9452 AN XY: 74266

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.0995

Gnomad4 ASJ AF: 0.0837

Gnomad4 EAS AF: 0.0985

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.119

Alfa AF: 0.143 Hom.: 971

Bravo AF: 0.114

TwinsUK AF: 0.167 AC: 619

ALSPAC AF: 0.176 AC: 680

ESP6500AA AF: 0.0458 AC: 174

ESP6500EA AF: 0.156 AC: 1278

ExAC AF: 0.140 AC: 16850

Asia WGS AF: 0.147 AC: 514 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2020

This variant is associated with the following publications: (PMID: 14741193) -

CAPN10-related disorder 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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.015
DANN	Benign	0.24
DEOGEN2	Benign	0.074	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.22	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.77	N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.45	N;N
REVEL	Benign	0.22
Sift	Benign	0.82	T;T
Sift4G	Benign	0.99	T;T
Polyphen		0.0	B;B
Vest4		0.031
MPC		0.34
ClinPred		0.000014	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.21

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: rs7607759; hg19: chr2-241536126; COSMIC: COSV54379647; COSMIC: COSV54379647;