Genetic Variant NM_001137667.2:c.490C>T (chr6-89862199-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001137667.2(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. 9/11 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_001137667.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.557

Publications

0 publications found

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: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137667.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP8AP2	NM_001137667.2	MANE Select	c.490C>T	p.Leu164Phe	missense	Exon 7 of 10	NP_001131139.1	Q9UKL3
CASP8AP2	NM_001137668.2		c.490C>T	p.Leu164Phe	missense	Exon 7 of 10	NP_001131140.1	Q9UKL3
CASP8AP2	NM_012115.4		c.490C>T	p.Leu164Phe	missense	Exon 7 of 10	NP_036247.1	Q9UKL3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP8AP2	ENST00000551025.4	TSL:1	c.490C>T	p.Leu164Phe	missense	Exon 7 of 9	ENSP00000478179.2	A0A087WTW5
CASP8AP2	ENST00000552401.5	TSL:1	c.490C>T	p.Leu164Phe	missense	Exon 7 of 7	ENSP00000485346.1	A0A096LP21
CASP8AP2	ENST00000419040.6	TSL:2	c.490C>T	p.Leu164Phe	missense	Exon 7 of 7	ENSP00000485349.1	A0A096LP21

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

GnomAD2 exomes

AF:

0.000111

AC:

AN:

243566

AF XY:

0.000152

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:

0.00000898

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

African (AFR)

AF:

0.00

AC:

AN:

25962

American (AMR)

AF:

0.00

AC:

AN:

35860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16676

East Asian (EAS)

AF:

0.00

AC:

AN:

16716

South Asian (SAS)

AF:

0.00119

AC:

AN:

81512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32496

Middle Eastern (MID)

AF:

0.000451

AC:

AN:

4432

European-Non Finnish (NFE)

AF:

0.00000105

AC:

AN:

950828

Other (OTH)

AF:

0.0000457

AC:

AN:

43746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41520

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000182

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.5

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.65

MetaRNN

Benign

0.015

PhyloP100

-0.56

PrimateAI

Benign

0.28

Sift4G

Benign

0.96

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over