Genetic Variant CAPN3:p.Tyr401Cys (chr15-42399500-AT-GC) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

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

The NM_000070.3(CAPN3):c.1202_1203delATinsGC (p.Tyr401Cys) 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.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: not found (cov: 31)

Consequence

CAPN3
NM_000070.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.36

Publications

0 publications found

Variant links:

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

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

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new If you want to explore the variant's impact on the transcript NM_000070.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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.

Show applied only (3)

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

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
CAPN3 NM_000070.3	MANE Select	c.1202_1203delATinsGC p.Tyr401Cys	missense	N/A	Prot: NP_000061.1 UniProt: P20807-1
CAPN3 NM_024344.2		c.1202_1203delATinsGC p.Tyr401Cys	missense	N/A	Prot: NP_077320.1 UniProt: P20807-3
CAPN3 NM_173087.2		c.1058_1059delATinsGC p.Tyr353Cys	missense	N/A	Prot: NP_775110.1 UniProt: P20807-2

CAPN3 NM_000070.3

MANE Select

HGVSc / HGVSpc.1202_1203delATinsGCp.Tyr401Cys

Exon rankN/A

missense

Prot: NP_000061.1UniProt: P20807-1

CAPN3 NM_024344.2

HGVSc / HGVSpc.1202_1203delATinsGCp.Tyr401Cys

Exon rankN/A

missense

Prot: NP_077320.1UniProt: P20807-3

CAPN3 NM_173087.2

HGVSc / HGVSpc.1058_1059delATinsGCp.Tyr353Cys

Exon rankN/A

missense

Prot: NP_775110.1UniProt: P20807-2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
CAPN3 ENST00000397163.8	TSL:1MANE Select	c.1202_1203delATinsGC p.Tyr401Cys	missense	N/A	Prot: ENSP00000380349.3 UniProt: P20807-1
CAPN3 ENST00000357568.8	TSL:1	c.1202_1203delATinsGC p.Tyr401Cys	missense	N/A	Prot: ENSP00000350181.3 UniProt: P20807-3
CAPN3 ENST00000349748.8	TSL:1	c.1058_1059delATinsGC p.Tyr353Cys	missense	N/A	Prot: ENSP00000183936.4 UniProt: P20807-2

CAPN3 ENST00000397163.8

TSL:1MANE Select

HGVSc / HGVSpc.1202_1203delATinsGCp.Tyr401Cys

Exon rankN/A

missense

Prot: ENSP00000380349.3UniProt: P20807-1

CAPN3 ENST00000357568.8

TSL:1

HGVSc / HGVSpc.1202_1203delATinsGCp.Tyr401Cys

Exon rankN/A

missense

Prot: ENSP00000350181.3UniProt: P20807-3

CAPN3 ENST00000349748.8

TSL:1

HGVSc / HGVSpc.1058_1059delATinsGCp.Tyr353Cys

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence