2-31192012-C-T

Position:

• chr2-31192012-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145122.2(CAPN14):​c.1201G>A​(p.Val401Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,294 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CAPN14 NM_001145122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

CAPN14 (HGNC:16664): (calpain 14) Calpains are a family of cytosolic calcium-activated cysteine proteases involved in a variety of cellular processes including apoptosis, cell division, modulation of integrin-cytoskeletal interactions, and synaptic plasticity (Dear et al., 2000 [PubMed 10964513]). CAPN14 belongs to the calpain large subunit family.[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN14	NM_001145122.2	c.1201G>A	p.Val401Met	missense_variant	11/22	ENST00000403897.4	NP_001138594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN14	ENST00000403897.4	c.1201G>A	p.Val401Met	missense_variant	11/22	2	NM_001145122.2	ENSP00000385247	P1
CAPN14	ENST00000398824.6	c.*632G>A		3_prime_UTR_variant, NMD_transcript_variant	11/22	2		ENSP00000381805

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399294 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.1201G>A (p.V401M) alteration is located in exon 11 (coding exon 10) of the CAPN14 gene. This alteration results from a G to A substitution at nucleotide position 1201, causing the valine (V) at amino acid position 401 to be replaced by a methionine (M). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.69		Gain of catalytic residue at V401 (P = 0.04);
MVP		0.30
ClinPred		0.84	D
GERP RS		2.0
Varity_R		0.37
gMVP		0.67

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: rs1167740802; hg19: chr2-31414878;