15-42399500-A-G

Variant names:

• chr15-42399500-A-G
• rs371784007
• NM_000070.3:c.1202A>G
• CAPN3 p.Tyr401Cys

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACMG Germline Pathogenicity v2019). PM2PM5PP3_ModeratePP5

The NM_000070.3(CAPN3):c.1202A>G (p.Tyr401Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000013 (AC=21) in the gnomAD database across 1,613,008 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000811. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.Y401F: Likely_pathogenic (ClinVar VariationId 965033, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Y401H: Uncertain_significance (ClinVar VariationId 3719679, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 5.36
• Publications: 2 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):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Natera
• 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: Natera, Labcorp Genetics (formerly Invitae), Myriad Women's Health, Orphanet

ENSG00000258461 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Specifications for CAPN3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000811 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0031) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.Y401F: Likely_pathogenic (ClinVar VariationId 965033, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.Y401H: Uncertain_significance (ClinVar VariationId 3719679, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1202A>G	p.Tyr401Cys	missense	Exon 10 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.1202A>G	p.Tyr401Cys	missense	Exon 10 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.1058A>G	p.Tyr353Cys	missense	Exon 9 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1202A>G	p.Tyr401Cys	missense	Exon 10 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.1202A>G	p.Tyr401Cys	missense	Exon 10 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.1058A>G	p.Tyr353Cys	missense	Exon 9 of 21	ENSP00000183936.4	P20807-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152082	Cov:31
GnomAD2 exomes	AF: 0.00000795	AC:2	Hom:	AN:251462	Cov:
GnomAD4 exome	AF: 0.0000123	AC:18	Hom:0	AN:1460926	Cov:30
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152082	Cov:31
TOPMed (Bravo)	AF: 0.0000302	AC:8	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000598	AC:2	Hom:0	AN:33426	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13004	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000250	AC:3	Hom:0	AN:122296	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	77656	0.0000144	2	139294

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (4)
2	1	-	not provided (3)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.86
GPN-Star LLR	N/A	-7.5
GPN-Star score	N/A	7.5
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.48	D
Mutation Taster	N/A	2/98	disease causing
MutationAssessor	Benign	0.89	L
PhyloP100	Uncertain	5.4
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.84
VESM-3B	Benign	-9.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs371784007;

hg19: chr15-42691698;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar