rs146286958

chr2-201284905-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001372051.1(CASP8):c.892A>G(p.Ile298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,614,136 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: CASP8 NM_001372051.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.78

Genes affected

CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009804755).
• BP6: Variant 2-201284905-A-G is Benign according to our data. Variant chr2-201284905-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000591 (90/152246) while in subpopulation NFE AF= 0.000823 (56/68012). AF 95% confidence interval is 0.000651. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.892A>G	p.Ile298Val	missense_variant	8/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.892A>G	p.Ile298Val	missense_variant	8/9		NM_001372051.1	P1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000724 AC: 182 AN: 251486 Hom.: 0 AF XY: 0.000750 AC XY: 102 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000958

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000610 AC: 892 AN: 1461890 Hom.: 2 Cov.: 34 AF XY: 0.000605 AC XY: 440 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000579

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74450

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000574

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000791 AC: 96

EpiCase AF: 0.00109

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0010
Dann	Benign	0.46
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.086	T;T;T;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0098	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.40	N;N;N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.50	T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.
Vest4		0.13
MVP		0.55
MPC		0.25
ClinPred		0.021	T
GERP RS		-11
Varity_R		0.052
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs146286958; hg19: chr2-202149628; COSMIC: COSV99036158; COSMIC: COSV99036158;