15-42399600-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000397163.8(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. Synonymous variant affecting the same amino acid position (i.e. N434N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 ENST00000397163.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.55
• Publications: 0 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000397163.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397163.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1302C>A	p.Asn434Lys	missense	Exon 10 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.1302C>A	p.Asn434Lys	missense	Exon 10 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.1158C>A	p.Asn386Lys	missense	Exon 9 of 21	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1302C>A	p.Asn434Lys	missense	Exon 10 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1302C>A	p.Asn434Lys	missense	Exon 10 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1158C>A	p.Asn386Lys	missense	Exon 9 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.085	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.3	L
PhyloP100		-3.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.55
Sift	Benign	0.054	T
Sift4G	Benign	0.082	T
Polyphen		0.93	P
Vest4		0.80
MutPred		0.55		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

Other links and lift over

dbSNP: rs751429914; hg19: chr15-42691798;