1-223712678-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001748.5(CAPN2):c.38A>C(p.Glu13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CAPN2 NM_001748.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.998

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0656662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN2	NM_001748.5	c.38A>C	p.Glu13Ala	missense_variant	1/21	ENST00000295006.6
CAPN2	XM_047431344.1	c.38A>C	p.Glu13Ala	missense_variant	1/12
CAPN2	NM_001146068.2	c.4-5084A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN2	ENST00000295006.6	c.38A>C	p.Glu13Ala	missense_variant	1/21	1	NM_001748.5	P1
CAPN2	ENST00000433674.6	c.4-5084A>C		intron_variant		2
CAPN2	ENST00000434648.5	c.4-5084A>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1401772 Hom.: 0 Cov.: 29 AF XY: 0.00000144 AC XY: 1 AN XY: 693532

Gnomad4 AFR exome AF: 0.0000329

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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.38A>C (p.E13A) alteration is located in exon 1 (coding exon 1) of the CAPN2 gene. This alteration results from a A to C substitution at nucleotide position 38, causing the glutamic acid (E) at amino acid position 13 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.00054	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	14
Dann	Benign	0.75
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.066	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.35	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.25
Sift	Benign	0.81	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.32		Gain of helix (P = 0.0082);
MVP		0.80
MPC		0.15
ClinPred		0.053	T
GERP RS		0.23
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.2
Varity_R		0.15
gMVP		0.48

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: rs1297410443; hg19: chr1-223900380;