2-31177058-A-T

Position:

• chr2-31177058-A-T

Variant summary

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

The NM_001145122.2(CAPN14):​c.1940T>A​(p.Ile647Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CAPN14 NM_001145122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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.1940T>A	p.Ile647Asn	missense_variant	20/22	ENST00000403897.4	NP_001138594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN14	ENST00000403897.4	c.1940T>A	p.Ile647Asn	missense_variant	20/22	2	NM_001145122.2	ENSP00000385247.3
CAPN14	ENST00000398824.6	n.*1371T>A		non_coding_transcript_exon_variant	20/22	2		ENSP00000381805.2
CAPN14	ENST00000398824.6	n.*1371T>A		3_prime_UTR_variant	20/22	2		ENSP00000381805.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

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 12, 2021

The c.1940T>A (p.I647N) alteration is located in exon 20 (coding exon 19) of the CAPN14 gene. This alteration results from a T to A substitution at nucleotide position 1940, causing the isoleucine (I) at amino acid position 647 to be replaced by an asparagine (N). 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	0.29
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.45	P
Vest4		0.53
MutPred		0.69		Loss of stability (P = 0.0211);
MVP		0.11
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-31399924;