2-30742333-C-A

Position:

• chr2-30742333-C-A

Variant summary

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

The NM_144575.3(CAPN13):​c.1472G>T​(p.Arg491Ile) 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. 15/21 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: CAPN13 NM_144575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.85

Genes affected

CAPN13 (HGNC:16663): (calpain 13) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes a member of the calpain large subunit family. [provided by RefSeq, Jun 2012]

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=0.087169796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN13	NM_144575.3	c.1472G>T	p.Arg491Ile	missense_variant	14/23	ENST00000295055.12	NP_653176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN13	ENST00000295055.12	c.1472G>T	p.Arg491Ile	missense_variant	14/23	5	NM_144575.3	ENSP00000295055	P1
CAPN13	ENST00000450650.5	c.164G>T	p.Arg55Ile	missense_variant, NMD_transcript_variant	2/11	2		ENSP00000403180
CAPN13	ENST00000458085.6	c.*156G>T		3_prime_UTR_variant, NMD_transcript_variant	15/16	5		ENSP00000416191

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Mar 16, 2022

The c.1472G>T (p.R491I) alteration is located in exon 14 (coding exon 13) of the CAPN13 gene. This alteration results from a G to T substitution at nucleotide position 1472, causing the arginine (R) at amino acid position 491 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	3.0
DANN	Benign	0.92
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.19	T
Sift4G	Benign	0.41	T
Polyphen		0.29	B
Vest4		0.15
MutPred		0.41		Loss of disorder (P = 0.029);
MVP		0.48
MPC		0.20
ClinPred		0.13	T
GERP RS		0.0070
Varity_R		0.063
gMVP		0.28

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: chr2-30965199;