Genetic Variant NM_001143962.2:c.1775C>T (chr1-223545289-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

The NM_001143962.2(CAPN8):c.1775C>T(p.Thr592Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,550,914 control chromosomes in the GnomAD database, including 213,191 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.47 ( 17754 hom., cov: 32)

Exomes 𝑓: 0.53 ( 195437 hom. )

Consequence

CAPN8
NM_001143962.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Publications

18 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: Benign. The variant received -10 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity CAN8_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=5.6138635E-4).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN8	NM_001143962.2 link	c.1775C>T	p.Thr592Met	missense_variant	Exon 17 of 21	ENST00000366872.10	NP_001137434.1	A6NHC0
CAPN8	XM_017001265.2 link	c.1292C>T	p.Thr431Met	missense_variant	Exon 14 of 18		XP_016856754.1
CAPN8	XM_017001266.2 link	c.1094C>T	p.Thr365Met	missense_variant	Exon 12 of 16		XP_016856755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN8	ENST00000366872.10 link	c.1775C>T	p.Thr592Met	missense_variant	Exon 17 of 21	1	NM_001143962.2	ENSP00000355837.6	A6NHC0
CAPN8	ENST00000482401.6 link	n.86C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2
CAPN8	ENST00000442247.5 link	c.123+4029C>T		intron_variant	Intron 2 of 3	5		ENSP00000409233.1	A3QK36

Frequencies

GnomAD3 genomes

AF:

0.467

AC:

70964

AN:

151906

Hom.:

17749

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.436

Gnomad AMR

AF:

0.563

Gnomad ASJ

AF:

0.579

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.487

GnomAD2 exomes

AF:

0.534

AC:

83565

AN:

156486

AF XY:

0.529

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.617

Gnomad ASJ exome

AF:

0.587

Gnomad EAS exome

AF:

0.527

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.545

Gnomad OTH exome

AF:

0.530

GnomAD4 exome

AF:

0.527

AC:

736533

AN:

1398890

Hom.:

195437

Cov.:

AF XY:

0.527

AC XY:

363576

AN XY:

689998

show subpopulations

African (AFR)

AF:

0.266

AC:

8394

AN:

31590

American (AMR)

AF:

0.606

AC:

21632

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.588

AC:

14797

AN:

25178

East Asian (EAS)

AF:

0.514

AC:

18365

AN:

35736

South Asian (SAS)

AF:

0.488

AC:

38657

AN:

79230

European-Finnish (FIN)

AF:

0.544

AC:

26818

AN:

49256

Middle Eastern (MID)

AF:

0.535

AC:

3046

AN:

5698

European-Non Finnish (NFE)

AF:

0.534

AC:

575494

AN:

1078524

Other (OTH)

AF:

0.506

AC:

29330

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

19467

38933

58400

77866

97333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16508

33016

49524

66032

82540

<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:

0.467

AC:

71000

AN:

152024

Hom.:

17754

Cov.:

AF XY:

0.469

AC XY:

34819

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.267

AC:

11085

AN:

41472

American (AMR)

AF:

0.563

AC:

8604

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

2011

AN:

3472

East Asian (EAS)

AF:

0.531

AC:

2746

AN:

5170

South Asian (SAS)

AF:

0.476

AC:

2289

AN:

4810

European-Finnish (FIN)

AF:

0.551

AC:

5810

AN:

10552

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36890

AN:

67950

Other (OTH)

AF:

0.487

AC:

1028

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1829

3659

5488

7318

9147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.512

Hom.:

34298

Bravo

AF:

0.462

TwinsUK

AF:

0.530

AC:

1967

ALSPAC

AF:

0.531

AC:

2047

ESP6500AA

AF:

0.252

AC:

349

ESP6500EA

AF:

0.545

AC:

1733

ExAC

AF:

0.486

AC:

11544

Asia WGS

AF:

0.451

AC:

1569

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

0.13

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.00056

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.0

M;.

PhyloP100

1.3

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.7

.;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.011

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.061

MPC

0.0019

ClinPred

0.037

GERP RS

3.5

Varity_R

0.018

gMVP

0.40

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over