dbSNP rs371046529: CASP8AP2:p.Asp173Asn (chr6-89862226-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012115.4(CASP8AP2):c.517G>A(p.Asp173Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,213,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CASP8AP2
NM_012115.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20993018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CASP8AP2	NM_001137667.2 link	c.517G>A	p.Asp173Asn	missense_variant	Exon 7 of 10	NP_001131139.1	Q9UKL3
CASP8AP2	NM_001137668.2 link	c.517G>A	p.Asp173Asn	missense_variant	Exon 7 of 10	NP_001131140.1	Q9UKL3
CASP8AP2	NM_012115.4 link	c.517G>A	p.Asp173Asn	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.517G>A	p.Asp173Asn	missense_variant	Exon 7 of 9	1		ENSP00000478179.2		A0A087WTW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248424

AF XY:

0.0000148

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000115

AC:

AN:

1213250

Hom.:

Cov.:

AF XY:

0.00000998

AC XY:

AN XY:

601214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26262

American (AMR)

AF:

0.00

AC:

AN:

37170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16852

East Asian (EAS)

AF:

0.00

AC:

AN:

16776

South Asian (SAS)

AF:

0.00

AC:

AN:

82884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4468

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

952352

Other (OTH)

AF:

0.00

AC:

AN:

43926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

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

Jun 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.517G>A (p.D173N) alteration is located in exon 1 (coding exon 1) of the CASP8AP2 gene. This alteration results from a G to A substitution at nucleotide position 517, causing the aspartic acid (D) at amino acid position 173 to be replaced by an asparagine (N). 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

-0.20

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.038

.;.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

.;T;T

MetaRNN

Benign

0.21

T;T;T

PhyloP100

2.1

PrimateAI

Benign

0.38

Sift4G

Benign

0.14

T;T;T

MVP

0.76

GERP RS

3.7

gMVP

0.13

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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rs371046529

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over