dbSNP rs886042108: CAPN3:c.2051-1G>A (chr15-42409930-G-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000070.3(CAPN3):c.2051-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

no classifications from unflagged records no classifications from unflagged records P:1

Conservation

PhyloP100: 10.0

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 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.1, offset of 5, new splice context is: tctccatccccccaaacaAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-42409930-G-A is Pathogenic according to our data. Variant chr15-42409930-G-A is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 2680393.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.2051-1G>A		splice_acceptor_variant, intron_variant	Intron 18 of 23	ENST00000397163.8	NP_000061.1	P20807-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.2051-1G>A	splice_acceptor_variant, intron_variant	Intron 18 of 23	1	NM_000070.3	ENSP00000380349.3	P20807-1
CAPN3	ENST00000673886.1 link	c.56-1G>A	splice_acceptor_variant, intron_variant	Intron 5 of 10			ENSP00000501155.1	P20807-5
CAPN3	ENST00000673928.1 link	c.56-1G>A	splice_acceptor_variant, intron_variant	Intron 5 of 10			ENSP00000501099.1	P20807-5
CAPN3	ENST00000674146.1 link	c.56-1G>A	splice_acceptor_variant, intron_variant	Intron 6 of 11			ENSP00000501175.1	P20807-5
CAPN3	ENST00000674149.1 link	c.56-1G>A	splice_acceptor_variant, intron_variant	Intron 5 of 10			ENSP00000501112.1	P20807-5
CAPN3	ENST00000673743.1 link	c.-42-6G>A	splice_region_variant, intron_variant	Intron 5 of 10			ENSP00000500989.1	A0A669KAX6
ENSG00000258461	ENST00000495723.1 link	n.*2487-1G>A	splice_acceptor_variant, intron_variant	Intron 20 of 25	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

LINK: link

Submissions by phenotype

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Oct 28, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.76

Position offset: 6

DS_AL_spliceai

0.99

Position offset: 1

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over