NM_000070.3:c.1202_1203delATinsTC

Variant names:

• chr15-42399500-AT-TC
• NM_000070.3:c.1202_1203delATinsTC
• CAPN3 p.Tyr401Phe

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_SupportingO8_Supporting

The NM_000070.3(CAPN3):c.1202_1203delATinsTC (p.Tyr401Phe) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.Y401C: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 553468) 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: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36
• 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):

• 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 ACGS-UK Somatic Oncogenicity v2025

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: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 1 pathogenic, 0 benign (OR vs. background: 15.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.86 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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.1202_1203delATinsTC p.Tyr401Phe	missense	N/A	Prot: NP_000061.1 UniProt:
	CAPN3 NM_024344.2		c.1202_1203delATinsTC p.Tyr401Phe	missense	N/A	Prot: NP_077320.1 UniProt:
	CAPN3 NM_173087.2		c.1058_1059delATinsTC p.Tyr353Phe	missense	N/A	Prot: NP_775110.1 UniProt:

CAPN3 NM_000070.3

MANE Select

HGVSc / HGVSpc.1202_1203delATinsTCp.Tyr401Phe

Exon rankN/A

missense

Prot: NP_000061.1UniProt: P20807-1

CAPN3 NM_024344.2

HGVSc / HGVSpc.1202_1203delATinsTCp.Tyr401Phe

Exon rankN/A

missense

Prot: NP_077320.1UniProt: P20807-3

CAPN3 NM_173087.2

HGVSc / HGVSpc.1058_1059delATinsTCp.Tyr353Phe

Exon rankN/A

missense

Prot: NP_775110.1UniProt: P20807-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CAPN3 ENST00000397163.8	TSL:1MANE Select	c.1202_1203delATinsTC p.Tyr401Phe	missense	N/A	Prot: ENSP00000380349.3 UniProt:
	CAPN3 ENST00000357568.8	TSL:1	c.1202_1203delATinsTC p.Tyr401Phe	missense	N/A	Prot: ENSP00000350181.3 UniProt:
	CAPN3 ENST00000349748.8	TSL:1	c.1058_1059delATinsTC p.Tyr353Phe	missense	N/A	Prot: ENSP00000183936.4 UniProt:

CAPN3 ENST00000397163.8

TSL:1MANE Select

HGVSc / HGVSpc.1202_1203delATinsTCp.Tyr401Phe

Exon rankN/A

missense

Prot: ENSP00000380349.3UniProt: P20807-1

CAPN3 ENST00000357568.8

TSL:1

HGVSc / HGVSpc.1202_1203delATinsTCp.Tyr401Phe

Exon rankN/A

missense

Prot: ENSP00000350181.3UniProt: P20807-3

CAPN3 ENST00000349748.8

TSL:1

HGVSc / HGVSpc.1058_1059delATinsTCp.Tyr353Phe

Exon rankN/A

missense

Prot: ENSP00000183936.4UniProt: 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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr15-42691698;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar