Genetic Variant NM_001143962.2:c.1145G>C (chr1-223616136-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001143962.2(CAPN8):c.1145G>C(p.Trp382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000502 in 1,394,278 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: 33)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN8	NM_001143962.2 link	c.1145G>C	p.Trp382Ser	missense_variant	Exon 10 of 21	ENST00000366872.10	NP_001137434.1	A6NHC0
CAPN8	XM_017001265.2 link	c.662G>C	p.Trp221Ser	missense_variant	Exon 7 of 18		XP_016856754.1
CAPN8	XM_017001266.2 link	c.464G>C	p.Trp155Ser	missense_variant	Exon 5 of 16		XP_016856755.1
CAPN8	XM_017001267.3 link	c.1311G>C	p.Leu437Leu	synonymous_variant	Exon 11 of 11		XP_016856756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN8	ENST00000366872.10 link	c.1145G>C	p.Trp382Ser	missense_variant	Exon 10 of 21	1	NM_001143962.2	ENSP00000355837.6		A6NHC0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000386

AC:

AN:

155540

AF XY:

0.0000608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000244

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000502

AC:

AN:

1394278

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

686396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31512

American (AMR)

AF:

0.000168

AC:

AN:

35616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35570

South Asian (SAS)

AF:

0.00

AC:

AN:

79000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1074770

Other (OTH)

AF:

0.00

AC:

AN:

57768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1145G>C (p.W382S) alteration is located in exon 1 (coding exon 1) of the CAPN8 gene. This alteration results from a G to C substitution at nucleotide position 1145, causing the tryptophan (W) at amino acid position 382 to be replaced by a serine (S). 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

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.0

M;.

PhyloP100

4.0

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-12

.;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

.;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.67

MutPred

0.86

Gain of disorder (P = 0.0158);Gain of disorder (P = 0.0158);

MVP

0.66

MPC

0.0017

ClinPred

0.98

GERP RS

5.2

Varity_R

0.39

gMVP

0.76

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over