ENST00000358485.8:c.41A>G

Variant names:

• chr2-201258272-A-G
• rs3769823
• ENST00000358485.8:c.41A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000358485.8(CASP8):​c.41A>G​(p.Lys14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,612,910 control chromosomes in the GnomAD database, including 387,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32194 hom., cov: 29)
  • Exomes 𝑓: 0.70 (355271 hom.)
• Consequence: CASP8 ENST00000358485.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.73
• Publications: 112 publications found

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]

CASP8 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.249959E-6).
• BP6: Variant 2-201258272-A-G is Benign according to our data. Variant chr2-201258272-A-G is described in ClinVar as Benign. ClinVar VariationId is 402492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358485.8. 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
	CASP8	NM_001080125.2		c.41A>G	p.Lys14Arg	missense	Exon 1 of 9	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.41A>G	p.Lys14Arg	missense	Exon 1 of 8	NP_001387571.1	A0A8Q3SID9
	CASP8	NM_001400665.1		c.41A>G	p.Lys14Arg	missense	Exon 1 of 6	NP_001387594.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000358485.8	TSL:1	c.41A>G	p.Lys14Arg	missense	Exon 1 of 9	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.-26-8189A>G		intron	N/A	ENSP00000264275.5	Q14790-4
	CASP8	ENST00000392258.7	TSL:1	c.-26-8189A>G		intron	N/A	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98187 AN: 151618 Hom.: 32170 Cov.: 29

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.749

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.660 AC: 164673 AN: 249496 AF XY: 0.666

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.577

Gnomad EAS exome AF: 0.710

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.647

GnomAD4 exome AF: 0.696 AC: 1016284 AN: 1461174 Hom.: 355271 Cov.: 50 AF XY: 0.695 AC XY: 505524 AN XY: 726898

African (AFR) AF: 0.565 AC: 18909 AN: 33472

American (AMR) AF: 0.544 AC: 24315 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 15254 AN: 26132

East Asian (EAS) AF: 0.699 AC: 27764 AN: 39696

South Asian (SAS) AF: 0.676 AC: 58291 AN: 86256

European-Finnish (FIN) AF: 0.650 AC: 34713 AN: 53410

Middle Eastern (MID) AF: 0.621 AC: 3583 AN: 5768

European-Non Finnish (NFE) AF: 0.713 AC: 792736 AN: 1111344

Other (OTH) AF: 0.674 AC: 40719 AN: 60376

GnomAD4 genome AF: 0.648 AC: 98265 AN: 151736 Hom.: 32194 Cov.: 29 AF XY: 0.644 AC XY: 47710 AN XY: 74122

African (AFR) AF: 0.577 AC: 23828 AN: 41298

American (AMR) AF: 0.564 AC: 8600 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2031 AN: 3470

East Asian (EAS) AF: 0.707 AC: 3645 AN: 5156

South Asian (SAS) AF: 0.682 AC: 3275 AN: 4804

European-Finnish (FIN) AF: 0.646 AC: 6791 AN: 10520

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47919 AN: 67926

Other (OTH) AF: 0.612 AC: 1288 AN: 2104

Alfa AF: 0.685 Hom.: 131864

Bravo AF: 0.637

TwinsUK AF: 0.723 AC: 2680

ALSPAC AF: 0.724 AC: 2791

ESP6500AA AF: 0.592 AC: 2286

ESP6500EA AF: 0.706 AC: 5832

ExAC AF: 0.667 AC: 80598

Asia WGS AF: 0.684 AC: 2380 AN: 3478

EpiCase AF: 0.692

EpiControl AF: 0.702

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autoimmune lymphoproliferative syndrome type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.97
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0080	B
Vest4		0.10
MPC		0.25
ClinPred		0.020	T
GERP RS		2.8
PromoterAI		-0.22	Neutral
gMVP		0.10
Mutation Taster		=100/0	polymorphism (auto)

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: rs3769823; hg19: chr2-202122995; COSMIC: COSV51848843; COSMIC: COSV51848843;