rs3792267

Variant names:

• chr2-240591757-G-A
• rs3792267
• NM_023083.4:c.471-176G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023083.4(CAPN10):​c.471-176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 615,740 control chromosomes in the GnomAD database, including 18,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (4176 hom., cov: 34)
  • Exomes 𝑓: 0.24 (14776 hom.)
• Consequence: CAPN10 NM_023083.4 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -3.50
• Publications: 81 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 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.471-176G>A		intron	N/A	NP_075571.2	Q9HC96-1
	CAPN10	NM_023085.4		c.471-176G>A		intron	N/A	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.471-176G>A		intron	N/A	ENSP00000375844.2	Q9HC96-1
	CAPN10	ENST00000354082.8	TSL:1	c.471-176G>A		intron	N/A	ENSP00000270362.6	Q9HC96-3
	CAPN10	ENST00000352879.8	TSL:1	c.141+4705G>A		intron	N/A	ENSP00000289381.6	Q9HC96-8

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34251 AN: 152182 Hom.: 4171 Cov.: 34

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.244 AC: 113000 AN: 463440 Hom.: 14776 Cov.: 5 AF XY: 0.243 AC XY: 58841 AN XY: 242506

African (AFR) AF: 0.147 AC: 1863 AN: 12698

American (AMR) AF: 0.305 AC: 5807 AN: 19036

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 3187 AN: 13860

East Asian (EAS) AF: 0.0707 AC: 2200 AN: 31106

South Asian (SAS) AF: 0.200 AC: 9013 AN: 45088

European-Finnish (FIN) AF: 0.232 AC: 7050 AN: 30446

Middle Eastern (MID) AF: 0.204 AC: 413 AN: 2026

European-Non Finnish (NFE) AF: 0.273 AC: 77230 AN: 282674

Other (OTH) AF: 0.235 AC: 6237 AN: 26506

GnomAD4 genome AF: 0.225 AC: 34270 AN: 152300 Hom.: 4176 Cov.: 34 AF XY: 0.223 AC XY: 16570 AN XY: 74468

African (AFR) AF: 0.147 AC: 6123 AN: 41566

American (AMR) AF: 0.279 AC: 4267 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 816 AN: 3466

East Asian (EAS) AF: 0.0811 AC: 421 AN: 5188

South Asian (SAS) AF: 0.185 AC: 894 AN: 4828

European-Finnish (FIN) AF: 0.222 AC: 2359 AN: 10618

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18524 AN: 68014

Other (OTH) AF: 0.228 AC: 481 AN: 2114

Alfa AF: 0.253 Hom.: 15418

Bravo AF: 0.224

Asia WGS AF: 0.131 AC: 454 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Type 2 diabetes mellitus 1, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.052
DANN	Benign	0.51
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3792267; hg19: chr2-241531174;