Variant chr1-223620222-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001143962.2(CAPN8):c.944T>C(p.Leu315Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000643 in 1,399,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.03

Variant links:

Genes affected

CAPN8 (HGNC:1485): (calpain 8) Predicted to enable calcium-dependent cysteine-type endopeptidase activity and identical protein binding activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within calcium-dependent self proteolysis. Predicted to be located in Golgi apparatus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CAPN8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN8	NM_001143962.2 linkuse as main transcript	c.944T>C	p.Leu315Pro	missense_variant	8/21	ENST00000366872.10	NP_001137434.1	A6NHC0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAPN8	ENST00000366872.10 linkuse as main transcript	c.944T>C	p.Leu315Pro	missense_variant	8/21	1	NM_001143962.2	ENSP00000355837.6	A6NHC0
CAPN8	ENST00000366873.6 linkuse as main transcript	c.944T>C	p.Leu315Pro	missense_variant	8/10	5		ENSP00000355838.2	B1B154
CAPN8	ENST00000467384.6 linkuse as main transcript	n.*741T>C		non_coding_transcript_exon_variant	8/8	5		ENSP00000434013.1	H0YDN4
CAPN8	ENST00000467384.6 linkuse as main transcript	n.*741T>C		3_prime_UTR_variant	8/8	5		ENSP00000434013.1	H0YDN4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

156562

Hom.:

AF XY:

0.0000121

AC XY:

AN XY:

82974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000330

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000643

AC:

AN:

1399396

Hom.:

Cov.:

AF XY:

0.00000724

AC XY:

AN XY:

690204

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:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.944T>C (p.L315P) alteration is located in exon 1 (coding exon 1) of the CAPN8 gene. This alteration results from a T to C substitution at nucleotide position 944, causing the leucine (L) at amino acid position 315 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;T;T

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.69

T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.3

.;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.027

.;D;D

Sift4G

Uncertain

0.035

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.53

MutPred

0.80

Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);

MVP

0.65

ClinPred

0.62

GERP RS

5.4

Varity_R

0.96

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over