6-89862260-A-T

Variant names:

• chr6-89862260-A-T
• rs777806066
• NM_001137667.2:c.551A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001137667.2(CASP8AP2):​c.551A>T​(p.Asp184Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,367,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CASP8AP2 NM_001137667.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8AP2	NM_001137667.2	MANE Select	c.551A>T	p.Asp184Val	missense	Exon 7 of 10	NP_001131139.1	Q9UKL3
	CASP8AP2	NM_001137668.2		c.551A>T	p.Asp184Val	missense	Exon 7 of 10	NP_001131140.1	Q9UKL3
	CASP8AP2	NM_012115.4		c.551A>T	p.Asp184Val	missense	Exon 7 of 10	NP_036247.1	Q9UKL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8AP2	ENST00000551025.4	TSL:1	c.551A>T	p.Asp184Val	missense	Exon 7 of 9	ENSP00000478179.2	A0A087WTW5
	CASP8AP2	ENST00000552401.5	TSL:1	c.551A>T	p.Asp184Val	missense	Exon 7 of 7	ENSP00000485346.1	A0A096LP21
	CASP8AP2	ENST00000419040.6	TSL:2	c.551A>T	p.Asp184Val	missense	Exon 7 of 7	ENSP00000485349.1	A0A096LP21

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 249018 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 18 AN: 1215242 Hom.: 0 Cov.: 32 AF XY: 0.0000149 AC XY: 9 AN XY: 602264

African (AFR) AF: 0.00 AC: 0 AN: 26294

American (AMR) AF: 0.0000268 AC: 1 AN: 37272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16894

East Asian (EAS) AF: 0.00 AC: 0 AN: 16804

South Asian (SAS) AF: 0.00 AC: 0 AN: 83182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4474

European-Non Finnish (NFE) AF: 0.0000178 AC: 17 AN: 953754

Other (OTH) AF: 0.00 AC: 0 AN: 43994

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.0000482 AC: 2 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Uncertain	0.56	D
PhyloP100		3.2
PrimateAI	Benign	0.38	T
Sift4G	Pathogenic	0.0	D
MVP		0.78
GERP RS		3.0
gMVP		0.32

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

Other links and lift over

dbSNP: rs777806066; hg19: chr6-90571979;