Genetic Variant CASP8AP2:p.Ala19Gly (chr6-89853166-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012115.4(CASP8AP2):c.56C>G(p.Ala19Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,353,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CASP8AP2
NM_012115.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.55

Variant links:

Genes affected

CASP8AP2 (HGNC:1510): (caspase 8 associated protein 2) This protein is highly similar to FLASH, a mouse apoptotic protein identified by its interaction with the death-effector domain (DED) of caspase 8. Studies of FLASH protein suggested that this protein may be a component of the death-inducing signaling complex that includes Fas receptor, Fas-binding adapter FADD, and caspase 8, and plays a regulatory role in Fas-mediated apoptosis. Alternative splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, Nov 2008]

CASP8AP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17271477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CASP8AP2	NM_001137667.2 link	c.56C>G	p.Ala19Gly	missense_variant, splice_region_variant	Exon 3 of 10	NP_001131139.1	Q9UKL3
CASP8AP2	NM_001137668.2 link	c.56C>G	p.Ala19Gly	missense_variant, splice_region_variant	Exon 3 of 10	NP_001131140.1	Q9UKL3
CASP8AP2	NM_012115.4 link	c.56C>G	p.Ala19Gly	missense_variant, splice_region_variant	Exon 3 of 10	NP_036247.1	Q9UKL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8AP2	ENST00000551025.4 link	c.56C>G	p.Ala19Gly	missense_variant, splice_region_variant	Exon 3 of 9	1		ENSP00000478179.2		A0A087WTW5

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000303

AC:

AN:

231250

Hom.:

AF XY:

0.0000321

AC XY:

AN XY:

124662

show subpopulations

Gnomad AFR exome

AF:

0.000491

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000749

AC:

AN:

1200810

Hom.:

Cov.:

AF XY:

0.00000842

AC XY:

AN XY:

593732

show subpopulations

Gnomad4 AFR exome

AF:

0.000344

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>G (p.A19G) alteration is located in exon 1 (coding exon 1) of the CASP8AP2 gene. This alteration results from a C to G substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 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

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.027

.;.;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.67

.;T;T

MetaRNN

Benign

0.17

T;T;T

PrimateAI

Uncertain

0.63

Sift4G

Pathogenic

0.0

D;D;D

MVP

0.69

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over