Genetic Variant CASP8AP2:p.Leu164Phe (chr6-89862199-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012115.4(CASP8AP2):c.490C>T(p.Leu164Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000801 in 1,360,442 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 2 hom. )

Consequence

CASP8AP2
NM_012115.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.557

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015416831).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CASP8AP2	NM_001137667.2 link	c.490C>T	p.Leu164Phe	missense_variant	Exon 7 of 10	NP_001131139.1	Q9UKL3
CASP8AP2	NM_001137668.2 link	c.490C>T	p.Leu164Phe	missense_variant	Exon 7 of 10	NP_001131140.1	Q9UKL3
CASP8AP2	NM_012115.4 link	c.490C>T	p.Leu164Phe	missense_variant	Exon 7 of 10	NP_036247.1	Q9UKL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8AP2	ENST00000551025.4 link	c.490C>T	p.Leu164Phe	missense_variant	Exon 7 of 9	1		ENSP00000478179.2		A0A087WTW5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152096

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:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

243566

Hom.:

AF XY:

0.000152

AC XY:

AN XY:

131886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000869

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000844

AC:

102

AN:

1208228

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

598298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000105

Gnomad4 OTH exome

AF:

0.0000457

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.000182

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.490C>T (p.L164F) alteration is located in exon 1 (coding exon 1) of the CASP8AP2 gene. This alteration results from a C to T substitution at nucleotide position 490, causing the leucine (L) at amino acid position 164 to be replaced by a phenylalanine (F). 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

-0.42

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.5

DANN

Benign

0.64

DEOGEN2

Benign

0.013

.;.;T

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.65

.;T;T

MetaRNN

Benign

0.015

T;T;T

PrimateAI

Benign

0.28

Sift4G

Benign

0.96

T;T;T

MVP

0.42

GERP RS

1.6

gMVP

0.023

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