15-42399601-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM5

The NM_000070.3(CAPN3):c.1303G>C(p.Glu435Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E435K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.06

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000070.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42399601-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1303G>C	p.Glu435Gln	missense_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1303G>C	p.Glu435Gln	missense_variant	10/23
CAPN3	NM_173087.2	c.1159G>C	p.Glu387Gln	missense_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1303G>C	p.Glu435Gln	missense_variant	10/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250332 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461388 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726958

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.79	T
REVEL	Pathogenic	0.70
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.93, 0.84, 0.94	.;P;P;P
Vest4		0.63
MutPred		0.66		.;Gain of MoRF binding (P = 0.02);.;Gain of MoRF binding (P = 0.02);
MVP		0.93
MPC		0.55
ClinPred		0.80	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149914792; hg19: chr15-42691799;