1-223747016-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001748.5(CAPN2):c.580G>T(p.Ala194Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CAPN2 NM_001748.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

Genes affected

CAPN2 (HGNC:1479): (calpain 2) 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 the large subunit of the ubiquitous enzyme, calpain 2. Multiple heterogeneous transcriptional start sites in the 5' UTR have been reported. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN2	NM_001748.5	c.580G>T	p.Ala194Ser	missense_variant	5/21	ENST00000295006.6
CAPN2	NM_001146068.2	c.346G>T	p.Ala116Ser	missense_variant	5/21
CAPN2	XM_047431344.1	c.580G>T	p.Ala194Ser	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6	c.580G>T	p.Ala194Ser	missense_variant	5/21	1	NM_001748.5	P1
CAPN2	ENST00000433674.6	c.346G>T	p.Ala116Ser	missense_variant	5/21	2
CAPN2	ENST00000434648.5	c.346G>T	p.Ala116Ser	missense_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

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

Oct 25, 2023

The c.580G>T (p.A194S) alteration is located in exon 5 (coding exon 5) of the CAPN2 gene. This alteration results from a G to T substitution at nucleotide position 580, causing the alanine (A) at amino acid position 194 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	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.046	D;D;D
Sift4G	Benign	0.099	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.38
MutPred		0.86		.;.;Gain of disorder (P = 0.034);
MVP		0.83
MPC		0.18
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs1660765816; hg19: chr1-223934718;