11-65182838-G-A

Variant summary

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

The NM_005186.4(CAPN1):c.137G>A(p.Arg46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,445,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CAPN1 NM_005186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

CAPN1 (HGNC:1476): (calpain 1) 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 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

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	UniProt
CAPN1	NM_005186.4	c.137G>A	p.Arg46Gln	missense_variant	2/22	ENST00000279247.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN1	ENST00000279247.11	c.137G>A	p.Arg46Gln	missense_variant	2/22	1	NM_005186.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000623 AC: 9 AN: 1445496 Hom.: 0 Cov.: 31 AF XY: 0.00000557 AC XY: 4 AN XY: 717628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000724

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The c.137G>A (p.R46Q) alteration is located in exon 2 (coding exon 1) of the CAPN1 gene. This alteration results from a G to A substitution at nucleotide position 137, causing the arginine (R) at amino acid position 46 to be replaced by a glutamine (Q). 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	0.078
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;D;T;T;D;D;D;.;T;.;T;.;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.84	T;T;.;.;D;.;.;.;D;D;T;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.090	T;T;D;T;T;D;D;D;D;T;T;T;T;D
Sift4G	Benign	0.061	T;D;T;T;T;T;T;T;D;D;D;D;D;T
Polyphen		0.021	.;.;B;.;.;B;B;B;.;.;.;.;.;B
Vest4		0.14, 0.13, 0.13, 0.14, 0.11
MutPred		0.55		Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);Loss of MoRF binding (P = 0.2295);
MVP		0.95
MPC		0.37
ClinPred		0.80	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.41		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs768464355; hg19: chr11-64950309;