2-240586936-C-T

Variant names:

• chr2-240586936-C-T
• rs2093071654
• NM_023083.4:c.25C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023083.4(CAPN10):​c.25C>T​(p.Pro9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,300,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: CAPN10 NM_023083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.308
• Publications: 0 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-DT (HGNC:48839): (CAPN10 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1840558).

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.25C>T	p.Pro9Ser	missense	Exon 1 of 12	NP_075571.2	Q9HC96-1
	CAPN10	NM_023085.4		c.25C>T	p.Pro9Ser	missense	Exon 1 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.25C>T	p.Pro9Ser	missense	Exon 1 of 12	ENSP00000375844.2	Q9HC96-1
	CAPN10	ENST00000354082.8	TSL:1	c.25C>T	p.Pro9Ser	missense	Exon 1 of 10	ENSP00000270362.6	Q9HC96-3
	CAPN10	ENST00000352879.8	TSL:1	c.25C>T	p.Pro9Ser	missense	Exon 1 of 4	ENSP00000289381.6	Q9HC96-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000384 AC: 5 AN: 1300406 Hom.: 0 Cov.: 31 AF XY: 0.00000313 AC XY: 2 AN XY: 639960

African (AFR) AF: 0.00 AC: 0 AN: 26064

American (AMR) AF: 0.00 AC: 0 AN: 21762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22670

East Asian (EAS) AF: 0.00 AC: 0 AN: 27762

South Asian (SAS) AF: 0.00 AC: 0 AN: 69866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 0.00000483 AC: 5 AN: 1035734

Other (OTH) AF: 0.00 AC: 0 AN: 53500

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.31
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.060	T
Sift4G	Uncertain	0.039	D
Polyphen		0.58	P
Vest4		0.13
MutPred		0.24		Gain of phosphorylation at P9 (P = 0.0202)
MVP		0.91
MPC		0.36
ClinPred		0.19	T
GERP RS		3.4
PromoterAI		0.099	Neutral
Varity_R		0.062
gMVP		0.28
Mutation Taster		=91/9	polymorphism

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: rs2093071654; hg19: chr2-241526353;