2-31174698-T-C

Position:

• chr2-31174698-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145122.2(CAPN14):​c.2038A>G​(p.Met680Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAPN14 NM_001145122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.694

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23952621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN14	NM_001145122.2	c.2038A>G	p.Met680Val	missense_variant	22/22	ENST00000403897.4	NP_001138594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN14	ENST00000403897.4	c.2038A>G	p.Met680Val	missense_variant	22/22	2	NM_001145122.2	ENSP00000385247	P1
CAPN14	ENST00000398824.6	c.*1469A>G		3_prime_UTR_variant, NMD_transcript_variant	22/22	2		ENSP00000381805

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jun 06, 2023

The c.2038A>G (p.M680V) alteration is located in exon 22 (coding exon 21) of the CAPN14 gene. This alteration results from a A to G substitution at nucleotide position 2038, causing the methionine (M) at amino acid position 680 to be replaced by a valine (V). 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	0.16
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	9.3
DANN	Benign	0.49
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.20
Sift	Benign	0.035	D
Sift4G	Benign	0.13	T
Polyphen		0.028	B
Vest4		0.48
MutPred		0.43		Loss of disorder (P = 0.0666);
MVP		0.061
ClinPred		0.062	T
GERP RS		0.61
Varity_R		0.10
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-31397564;