15-42410449-A-T

Variant names:

• chr15-42410449-A-T
• rs748363488
• NM_000070.3:c.2137A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000070.3(CAPN3):​c.2137A>T​(p.Asn713Tyr) 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. N713D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. 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.2137A>T	p.Asn713Tyr	missense	Exon 20 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.2119A>T	p.Asn707Tyr	missense	Exon 19 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.1861A>T	p.Asn621Tyr	missense	Exon 17 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.2137A>T	p.Asn713Tyr	missense	Exon 20 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.2119A>T	p.Asn707Tyr	missense	Exon 19 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1861A>T	p.Asn621Tyr	missense	Exon 17 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.58		Loss of disorder (P = 0.0719)
MVP		0.92
MPC		0.69
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.66
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs748363488; hg19: chr15-42702647;