rs187054121

Variant names:

• chr15-42409372-G-A
• NM_000070.3:c.1984G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-42409372-G-A
• chr15-42409372-G-C
• chr15-42409372-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000070.3(CAPN3):​c.1984G>A​(p.Ala662Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A662S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain EF-hand 1 (size 34) in uniprot entity CAN3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42409372-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1984G>A	p.Ala662Thr	missense_variant	Exon 17 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1984G>A	p.Ala662Thr	missense_variant	Exon 17 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886	c.-12G>A		5_prime_UTR_variant	Exon 4 of 11			ENSP00000501155.1
CAPN3	ENST00000673928	c.-12G>A		5_prime_UTR_variant	Exon 4 of 11			ENSP00000501099.1
CAPN3	ENST00000674146	c.-12G>A		5_prime_UTR_variant	Exon 5 of 12			ENSP00000501175.1
CAPN3	ENST00000674149	c.-12G>A		5_prime_UTR_variant	Exon 4 of 11			ENSP00000501112.1
CAPN3	ENST00000673743	c.-109G>A		5_prime_UTR_variant	Exon 4 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2420G>A		non_coding_transcript_exon_variant	Exon 19 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2420G>A		3_prime_UTR_variant	Exon 19 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.097	T;.;.;T;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;.;.;M;.;.;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.2	.;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;T;T;T;D;D;D
Polyphen		0.96, 0.95, 0.94	.;D;P;P;.;.;.
Vest4		0.89
MutPred		0.63		.;.;.;Gain of phosphorylation at A662 (P = 0.0409);.;.;.;
MVP		0.99
MPC		0.56
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42701570;