rs1555420495

Positions:

• chr15-42387829-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000070.3(CAPN3):​c.575C>T​(p.Thr192Ile) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T192S) has been classified 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: 5.03

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.575C>T	p.Thr192Ile	missense_variant	4/24	ENST00000397163.8
CAPN3	NM_024344.2	c.575C>T	p.Thr192Ile	missense_variant	4/23
CAPN3	NM_173087.2	c.575C>T	p.Thr192Ile	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.575C>T	p.Thr192Ile	missense_variant	4/24	1	NM_000070.3	P2

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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.088	T;.;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.60	.;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Benign	0.063	T;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.83
MutPred		0.82		Loss of ubiquitination at K193 (P = 0.0516);Loss of ubiquitination at K193 (P = 0.0516);Loss of ubiquitination at K193 (P = 0.0516);Loss of ubiquitination at K193 (P = 0.0516);
MVP		0.97
MPC		0.64
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.64
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555420495; hg19: chr15-42680027; COSMIC: COSV58821671;