6-89862212-C-G

Variant names:

• chr6-89862212-C-G
• rs779691993
• NM_001137667.2:c.503C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001137667.2(CASP8AP2):​c.503C>G​(p.Ser168Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000825 in 1,211,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S168Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: CASP8AP2 NM_001137667.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27183127).

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.503C>G	p.Ser168Cys	missense	Exon 7 of 10	NP_001131139.1	Q9UKL3
	CASP8AP2	NM_001137668.2		c.503C>G	p.Ser168Cys	missense	Exon 7 of 10	NP_001131140.1	Q9UKL3
	CASP8AP2	NM_012115.4		c.503C>G	p.Ser168Cys	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.503C>G	p.Ser168Cys	missense	Exon 7 of 9	ENSP00000478179.2	A0A087WTW5
	CASP8AP2	ENST00000552401.5	TSL:1	c.503C>G	p.Ser168Cys	missense	Exon 7 of 7	ENSP00000485346.1	A0A096LP21
	CASP8AP2	ENST00000419040.6	TSL:2	c.503C>G	p.Ser168Cys	missense	Exon 7 of 7	ENSP00000485349.1	A0A096LP21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247442 AF XY: 0.00000746

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.25e-7 AC: 1 AN: 1211812 Hom.: 0 Cov.: 29 AF XY: 0.00000167 AC XY: 1 AN XY: 600416

African (AFR) AF: 0.00 AC: 0 AN: 26172

American (AMR) AF: 0.00 AC: 0 AN: 36980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16842

East Asian (EAS) AF: 0.00 AC: 0 AN: 16764

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 951646

Other (OTH) AF: 0.00 AC: 0 AN: 43872

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.80
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.27	T
PhyloP100		2.2
PrimateAI	Benign	0.32	T
Sift4G	Uncertain	0.011	D
MVP		0.78
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.17

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: rs779691993; hg19: chr6-90571931;