6-89862256-A-T

Variant names:

• chr6-89862256-A-T
• ENST00000551025.4:c.547A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012115.4(CASP8AP2):​c.547A>T​(p.Ser183Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CASP8AP2 NM_012115.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24415007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP8AP2	NM_001137667.2	c.547A>T	p.Ser183Cys	missense_variant	Exon 7 of 10		NP_001131139.1
CASP8AP2	NM_001137668.2	c.547A>T	p.Ser183Cys	missense_variant	Exon 7 of 10		NP_001131140.1
CASP8AP2	NM_012115.4	c.547A>T	p.Ser183Cys	missense_variant	Exon 7 of 10		NP_036247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP8AP2	ENST00000551025.4	c.547A>T	p.Ser183Cys	missense_variant	Exon 7 of 9	1		ENSP00000478179.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547A>T (p.S183C) alteration is located in exon 1 (coding exon 1) of the CASP8AP2 gene. This alteration results from a A to T substitution at nucleotide position 547, causing the serine (S) at amino acid position 183 to be replaced by a cysteine (C). 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	0.0038	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.034	.;.;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	.;T;T
MetaRNN	Benign	0.24	T;T;T
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.0070	D;D;D
MVP		0.79
GERP RS		3.0
gMVP		0.086

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-90571975;