2-240586936-C-T

Position:

• chr2-240586936-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN10	NM_023083.4	c.25C>T	p.Pro9Ser	missense_variant	1/12	ENST00000391984.7
CAPN10	NM_023085.4	c.25C>T	p.Pro9Ser	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN10	ENST00000391984.7	c.25C>T	p.Pro9Ser	missense_variant	1/12	1	NM_023083.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000483

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.25C>T (p.P9S) alteration is located in exon 1 (coding exon 1) of the CAPN10 gene. This alteration results from a C to T substitution at nucleotide position 25, causing the proline (P) at amino acid position 9 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Uncertain	2.1	M;.;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.060	T;T;T;D;T
Sift4G	Uncertain	0.039	D;D;D;T;D
Polyphen		0.58	P;.;P;D;P
Vest4		0.13
MutPred		0.24		Gain of phosphorylation at P9 (P = 0.0202);Gain of phosphorylation at P9 (P = 0.0202);Gain of phosphorylation at P9 (P = 0.0202);Gain of phosphorylation at P9 (P = 0.0202);Gain of phosphorylation at P9 (P = 0.0202);
MVP		0.91
MPC		0.36
ClinPred		0.19	T
GERP RS		3.4
Varity_R		0.062
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs2093071654; hg19: chr2-241526353;