2-240592062-A-G

Variant names:

• chr2-240592062-A-G
• rs3792269
• NM_023083.4:c.600A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_023083.4(CAPN10):​c.600A>G​(p.Pro200Pro) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1450 hom., cov: 34)
  • Exomes 𝑓: 0.16 (19908 hom.)
• Consequence: CAPN10 NM_023083.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.53
• Publications: 32 publications found

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]

CAPN10 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -14 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 VariationId is 3056633.Status of the report is no_assertion_criteria_provided, 0 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023083.4. 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
	CAPN10	NM_023083.4	MANE Select	c.600A>G	p.Pro200Pro	synonymous	Exon 4 of 12	NP_075571.2	Q9HC96-1
	CAPN10	NM_023085.4		c.600A>G	p.Pro200Pro	synonymous	Exon 4 of 10	NP_075573.3	Q9HC96-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN10	ENST00000391984.7	TSL:1 MANE Select	c.600A>G	p.Pro200Pro	synonymous	Exon 4 of 12	ENSP00000375844.2	Q9HC96-1
	CAPN10	ENST00000354082.8	TSL:1	c.600A>G	p.Pro200Pro	synonymous	Exon 4 of 10	ENSP00000270362.6	Q9HC96-3
	CAPN10	ENST00000352879.8	TSL:1	c.141+5010A>G		intron	N/A	ENSP00000289381.6	Q9HC96-8

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

GnomAD2 exomes AF: 0.147 AC: 34872 AN: 237336 AF XY: 0.153

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 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

African (AFR) AF: 0.0416 AC: 1393 AN: 33462

American (AMR) AF: 0.0839 AC: 3668 AN: 43728

Ashkenazi Jewish (ASJ) AF: 0.0898 AC: 2323 AN: 25878

East Asian (EAS) AF: 0.0909 AC: 3585 AN: 39438

South Asian (SAS) AF: 0.192 AC: 16428 AN: 85384

European-Finnish (FIN) AF: 0.192 AC: 10022 AN: 52238

Middle Eastern (MID) AF: 0.139 AC: 803 AN: 5764

European-Non Finnish (NFE) AF: 0.169 AC: 188158 AN: 1110392

Other (OTH) AF: 0.151 AC: 9110 AN: 60182

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

African (AFR) AF: 0.0470 AC: 1955 AN: 41582

American (AMR) AF: 0.0992 AC: 1517 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 290 AN: 3472

East Asian (EAS) AF: 0.0986 AC: 510 AN: 5174

South Asian (SAS) AF: 0.194 AC: 935 AN: 4828

European-Finnish (FIN) AF: 0.189 AC: 2005 AN: 10608

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11508 AN: 68014

Other (OTH) AF: 0.118 AC: 250 AN: 2110

Alfa AF: 0.150 Hom.: 5633

Bravo AF: 0.114

Asia WGS AF: 0.147 AC: 512 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CAPN10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.23
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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