10-113697602-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_001227.5(CASP7):c.109A>G(p.Ser37Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,606,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CASP7
NM_001227.5 missense, splice_region

Scores

Splicing: ADA: 0.008970

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.218

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: Likely_benign. The variant received -6 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity CASP7_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.03554392).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP7	NM_001227.5 link	c.109A>G	p.Ser37Gly	missense_variant, splice_region_variant	Exon 2 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.109A>G	p.Ser37Gly	missense_variant, splice_region_variant	Exon 2 of 7	1	NM_001227.5	ENSP00000358324.4		P55210-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000558

AC:

AN:

251118

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000687

AC:

AN:

1454616

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

724194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33328

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.000227

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105374

Other (OTH)

AF:

0.00

AC:

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.208A>G (p.S70G) alteration is located in exon 3 (coding exon 2) of the CASP7 gene. This alteration results from a A to G substitution at nucleotide position 208, causing the serine (S) at amino acid position 70 to be replaced by a glycine (G). 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

Benign

0.062

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.5

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.061

T;T;.;T;.;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.44

T;T;.;.;T;.;.;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.036

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

M;.;M;M;M;M;M;.

PhyloP100

-0.22

PROVEAN

Benign

-1.1

.;N;N;N;.;N;N;.

REVEL

Benign

0.031

Sift

Benign

0.74

.;T;T;T;.;T;T;.

Sift4G

Benign

0.39

T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;B;B;B;B;B;B

Vest4

0.059

MutPred

0.27

Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);.;

MVP

0.35

ClinPred

0.94

GERP RS

-0.24

Varity_R

0.023

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0090

dbscSNV1_RF

Benign

0.25

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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10-113697602-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over