rs1555417328

Positions:

• chr15-42360040-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000070.3(CAPN3):​c.235G>C​(p.Glu79Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.235G>C	p.Glu79Gln	missense_variant	1/24	ENST00000397163.8
CAPN3	NM_024344.2	c.235G>C	p.Glu79Gln	missense_variant	1/23
CAPN3	NM_173087.2	c.235G>C	p.Glu79Gln	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.235G>C	p.Glu79Gln	missense_variant	1/24	1	NM_000070.3	P2
CAPN3	ENST00000357568.8	c.235G>C	p.Glu79Gln	missense_variant	1/23	1
CAPN3	ENST00000349748.8	c.235G>C	p.Glu79Gln	missense_variant	1/21	1
CAPN3	ENST00000318023.11	c.235G>C	p.Glu79Gln	missense_variant	1/23	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Feb 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.4	.;L;L;L
MutationTaster	Benign	0.52	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.56	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.14, 0.17	.;B;B;B
Vest4		0.20
MutPred		0.76		Loss of solvent accessibility (P = 0.0721);Loss of solvent accessibility (P = 0.0721);Loss of solvent accessibility (P = 0.0721);Loss of solvent accessibility (P = 0.0721);
MVP		0.92
MPC		0.23
ClinPred		0.41	T
GERP RS		6.0
Varity_R		0.45
gMVP		0.55

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: rs1555417328; hg19: chr15-42652238;