15-42360064-C-T

Position:

• chr15-42360064-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000397163.8(CAPN3):​c.259C>T​(p.Leu87Phe) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L87V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 ENST00000397163.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.10

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000397163.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42360064-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.259C>T	p.Leu87Phe	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.259C>T	p.Leu87Phe	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.259C>T	p.Leu87Phe	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.259C>T	p.Leu87Phe	missense_variant	1/24	1	NM_000070.3	ENSP00000380349	P2
CAPN3	ENST00000357568.8	c.259C>T	p.Leu87Phe	missense_variant	1/23	1		ENSP00000350181
CAPN3	ENST00000349748.8	c.259C>T	p.Leu87Phe	missense_variant	1/21	1		ENSP00000183936
CAPN3	ENST00000318023.11	c.259C>T	p.Leu87Phe	missense_variant	1/23	5		ENSP00000326281	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.84
MutPred		0.92		Gain of phosphorylation at T85 (P = 0.1438);Gain of phosphorylation at T85 (P = 0.1438);Gain of phosphorylation at T85 (P = 0.1438);Gain of phosphorylation at T85 (P = 0.1438);
MVP		0.99
MPC		0.65
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.94
gMVP		0.86

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: rs558925493; hg19: chr15-42652262;