NM_000070.3:c.1302C>A

Variant names:

• chr15-42399600-C-A
• rs751429914
• NM_000070.3:c.1302C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000070.3(CAPN3):​c.1302C>A​(p.Asn434Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. N434I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.55

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 7 ACMG points.

• PM1: In a region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 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 chr15-42399599-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1302C>A	p.Asn434Lys	missense_variant	Exon 10 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1302C>A	p.Asn434Lys	missense_variant	Exon 10 of 23		NP_077320.1
CAPN3	NM_173087.2	c.1158C>A	p.Asn386Lys	missense_variant	Exon 9 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1302C>A	p.Asn434Lys	missense_variant	Exon 10 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1098C>A		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1098C>A		3_prime_UTR_variant	Exon 14 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.026
DANN	Benign	0.97
DEOGEN2	Benign	0.058	T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.085	N
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.3	.;L;.;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.4	.;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.054	.;T;D;T
Sift4G	Benign	0.082	T;T;T;T
Polyphen		0.93, 0.93, 0.95	.;P;P;P
Vest4		0.80
MutPred		0.55		.;Gain of ubiquitination at N434 (P = 0.0192);.;Gain of ubiquitination at N434 (P = 0.0192);
MVP		0.64
MPC		0.64
ClinPred		0.85	D
GERP RS		-11
Varity_R		0.43
gMVP		0.74

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: rs751429914; hg19: chr15-42691798;