Genetic Variant ENST00000369331.8:c.746G>A (chr10-113729408-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000369331.8(CASP7):c.746G>A(p.Arg249Lys) variant causes a missense change. The variant allele was found at a frequency of 0.258 in 1,613,318 control chromosomes in the GnomAD database, including 55,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4392 hom., cov: 32)

Exomes 𝑓: 0.26 ( 50863 hom. )

Consequence

CASP7
ENST00000369331.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.10

Publications

46 publications found

Variant links:

Genes affected

CASP7 (HGNC:1508): (caspase 7) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. The precursor of the encoded protein is cleaved by caspase 3 and 10, is activated upon cell death stimuli and induces apoptosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

CASP7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026726127).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP7	NM_001227.5 link	c.780G>A	p.Gln260Gln	synonymous_variant	Exon 7 of 7	ENST00000369318.8	NP_001218.1	P55210-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP7	ENST00000369318.8 link	c.780G>A	p.Gln260Gln	synonymous_variant	Exon 7 of 7	1	NM_001227.5	ENSP00000358324.4		P55210-1

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35146

AN:

151982

Hom.:

4386

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.412

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.224

GnomAD2 exomes

AF:

0.261

AC:

65643

AN:

251410

AF XY:

0.259

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.277

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.260

AC:

380324

AN:

1461216

Hom.:

50863

Cov.:

AF XY:

0.259

AC XY:

188395

AN XY:

726964

show subpopulations

African (AFR)

AF:

0.143

AC:

4789

AN:

33470

American (AMR)

AF:

0.277

AC:

12369

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5098

AN:

26134

East Asian (EAS)

AF:

0.439

AC:

17410

AN:

39698

South Asian (SAS)

AF:

0.235

AC:

20306

AN:

86246

European-Finnish (FIN)

AF:

0.274

AC:

14625

AN:

53408

Middle Eastern (MID)

AF:

0.232

AC:

1337

AN:

5766

European-Non Finnish (NFE)

AF:

0.260

AC:

289476

AN:

1111384

Other (OTH)

AF:

0.247

AC:

14914

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

15892

31783

47675

63566

79458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9830

19660

29490

39320

49150

<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:

0.231

AC:

35166

AN:

152102

Hom.:

4392

Cov.:

AF XY:

0.232

AC XY:

17257

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.146

AC:

6069

AN:

41508

American (AMR)

AF:

0.239

AC:

3647

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

636

AN:

3472

East Asian (EAS)

AF:

0.412

AC:

2123

AN:

5156

South Asian (SAS)

AF:

0.237

AC:

1141

AN:

4812

European-Finnish (FIN)

AF:

0.271

AC:

2869

AN:

10570

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.262

AC:

17787

AN:

67978

Other (OTH)

AF:

0.225

AC:

475

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1377

2753

4130

5506

6883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.247

Hom.:

14624

Bravo

AF:

0.226

TwinsUK

AF:

0.241

AC:

895

ALSPAC

AF:

0.266

AC:

1027

ESP6500AA

AF:

0.148

AC:

652

ESP6500EA

AF:

0.253

AC:

2173

ExAC

AF:

0.260

AC:

31503

Asia WGS

AF:

0.277

AC:

965

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.245

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.3

(source)

DANN

Benign

0.95

Eigen

Benign

0.055

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.35

.;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.93

PhyloP100

4.1

PROVEAN

Benign

0.060

N;.

REVEL

Benign

0.032

Sift

Benign

1.0

T;.

Polyphen

0.18

B;B

Vest4

0.24

ClinPred

0.012

GERP RS

4.0

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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