chr2-240591746-T-C

Position:

• chr2-240591746-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023083.4(CAPN10):​c.471-187T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 605,384 control chromosomes in the GnomAD database, including 7,381 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 0.13 (1455 hom., cov: 34)
  • Exomes 𝑓: 0.16 (5926 hom.)
• Consequence: CAPN10 NM_023083.4 intron
• Clinical Significance: risk factor no assertion criteria provided O:2
• Conservation: PhyloP100: -3.31

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• 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	Protein	UniProt
CAPN10	NM_023083.4	c.471-187T>C		intron_variant		ENST00000391984.7	NP_075571.2
CAPN10	NM_023085.4	c.471-187T>C		intron_variant			NP_075573.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7	c.471-187T>C		intron_variant		1	NM_023083.4	ENSP00000375844	P1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19152 AN: 152150 Hom.: 1454 Cov.: 34

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.0993

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0981

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

GnomAD4 exome AF: 0.156 AC: 70693 AN: 453116 Hom.: 5926 Cov.: 5 AF XY: 0.157 AC XY: 37330 AN XY: 237166

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.0936

Gnomad4 ASJ exome AF: 0.0909

Gnomad4 EAS exome AF: 0.0904

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.126 AC: 19162 AN: 152268 Hom.: 1455 Cov.: 34 AF XY: 0.127 AC XY: 9460 AN XY: 74432

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.0993

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0983

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.118

Alfa AF: 0.137 Hom.: 331

Bravo AF: 0.114

Asia WGS AF: 0.147 AC: 513 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

POLYCYSTIC OVARY SYNDROME, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

Type 2 diabetes mellitus 1, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.6
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2975760; hg19: chr2-241531163;