Genetic Variant CAPN8:p.Ser245Cys (chr1-223625884-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001143962.2(CAPN8):c.734C>G(p.Ser245Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,550,710 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.00

Publications

23 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN8	NM_001143962.2	MANE Select	c.734C>G	p.Ser245Cys	missense	Exon 6 of 21	NP_001137434.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAPN8	ENST00000366872.10	TSL:1 MANE Select	c.734C>G	p.Ser245Cys	missense	Exon 6 of 21	ENSP00000355837.6
CAPN8	ENST00000366873.6	TSL:5	c.734C>G	p.Ser245Cys	missense	Exon 6 of 10	ENSP00000355838.2
CAPN8	ENST00000465098.1	TSL:3	c.350C>G	p.Ser117Cys	missense	Exon 4 of 5	ENSP00000435953.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1398744

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31596

American (AMR)

AF:

0.00

AC:

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35708

South Asian (SAS)

AF:

0.00

AC:

AN:

79208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078440

Other (OTH)

AF:

0.00

AC:

AN:

57972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

AF:

0.00000658

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41352

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

47635

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.0069

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.0

PhyloP100

8.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.18

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.17

MutPred

0.61

Loss of disorder (P = 0.0049)

MVP

0.39

MPC

0.0027

ClinPred

0.97

GERP RS

4.4

Varity_R

0.34

gMVP

0.48

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over