rs2975760

Variant names:

• chr2-240591746-T-C
• rs2975760
• NM_023083.4:c.471-187T>C

Variant summary

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

The NM_023083.4(CAPN10):​c.471-187T>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
• Publications: 56 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=-1.03).
• 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.471-187T>C		intron	N/A	NP_075571.2	Q9HC96-1
	CAPN10	NM_023085.4		c.471-187T>C		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.471-187T>C		intron	N/A	ENSP00000375844.2	Q9HC96-1
	CAPN10	ENST00000354082.8	TSL:1	c.471-187T>C		intron	N/A	ENSP00000270362.6	Q9HC96-3
	CAPN10	ENST00000352879.8	TSL:1	c.141+4694T>C		intron	N/A	ENSP00000289381.6	Q9HC96-8

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

African (AFR) AF: 0.0454 AC: 570 AN: 12544

American (AMR) AF: 0.0936 AC: 1758 AN: 18776

Ashkenazi Jewish (ASJ) AF: 0.0909 AC: 1251 AN: 13762

East Asian (EAS) AF: 0.0904 AC: 2803 AN: 31010

South Asian (SAS) AF: 0.188 AC: 8333 AN: 44232

European-Finnish (FIN) AF: 0.192 AC: 5755 AN: 29966

Middle Eastern (MID) AF: 0.149 AC: 296 AN: 1986

European-Non Finnish (NFE) AF: 0.168 AC: 46070 AN: 274690

Other (OTH) AF: 0.147 AC: 3857 AN: 26150

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

African (AFR) AF: 0.0471 AC: 1957 AN: 41568

American (AMR) AF: 0.0993 AC: 1518 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.0983 AC: 510 AN: 5186

South Asian (SAS) AF: 0.194 AC: 935 AN: 4826

European-Finnish (FIN) AF: 0.190 AC: 2016 AN: 10592

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

European-Non Finnish (NFE) AF: 0.169 AC: 11513 AN: 68022

Other (OTH) AF: 0.118 AC: 250 AN: 2114

Alfa AF: 0.105 Hom.: 353

Bravo AF: 0.114

Asia WGS AF: 0.147 AC: 513 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	POLYCYSTIC OVARY SYNDROME, SUSCEPTIBILITY TO (1)
-	-	-	Type 2 diabetes mellitus 1, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.6
DANN	Benign	0.31
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2975760; hg19: chr2-241531163;