rs35976359

chr2-201274948-T-Achr2-201274948-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001372051.1(CASP8):c.655T>A(p.Ser219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,608,962 control chromosomes in the GnomAD database, including 5 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S219A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: CASP8 NM_001372051.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053839684).
• BP6: Variant 2-201274948-T-A is Benign according to our data. Variant chr2-201274948-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 791745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00219 (333/152126) while in subpopulation AFR AF= 0.00752 (312/41500). AF 95% confidence interval is 0.00683. There are 4 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP8	NM_001372051.1	c.655T>A	p.Ser219Thr	missense_variant	6/9	ENST00000673742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000673742.1	c.655T>A	p.Ser219Thr	missense_variant	6/9		NM_001372051.1	P1
	ENST00000696101.1	n.480T>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152020 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00754

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000573 AC: 144 AN: 251304 Hom.: 1 AF XY: 0.000427 AC XY: 58 AN XY: 135822

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000213 AC: 310 AN: 1456836 Hom.: 1 Cov.: 28 AF XY: 0.000182 AC XY: 132 AN XY: 725112

Gnomad4 AFR exome AF: 0.00780

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000399

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152126 Hom.: 4 Cov.: 32 AF XY: 0.00225 AC XY: 167 AN XY: 74360

Gnomad4 AFR AF: 0.00752

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.00261

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.0
Dann	Benign	0.76
DEOGEN2	Benign	0.098	T;.;T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.69	T;T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.0054	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.38	N;N;N;N;.;N
REVEL	Benign	0.011
Sift	Benign	0.24	T;T;T;T;.;T
Sift4G	Benign	0.51	T;T;T;T;T;T
Polyphen		0.0090	B;B;.;B;.;B
Vest4		0.11
MVP		0.78
MPC		0.28
ClinPred		0.0073	T
GERP RS		-0.15
Varity_R		0.041
gMVP		0.35

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: rs35976359; hg19: chr2-202139671;