2-201185834-C-G

Position:

• chr2-201185834-C-G

Variant summary

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

The NM_032977.4(CASP10):​c.57C>G​(p.Ser19Arg) 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. 16/21 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: CASP10 NM_032977.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.918

Genes affected

CASP10 (HGNC:1500): (caspase 10) This gene encodes a protein which is 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 which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with type IIA autoimmune lymphoproliferative syndrome, non-Hodgkin lymphoma and gastric cancer. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

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=0.18275362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP10	NM_032977.4	c.57C>G	p.Ser19Arg	missense_variant	2/10	ENST00000286186.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP10	ENST00000286186.11	c.57C>G	p.Ser19Arg	missense_variant	2/10	1	NM_032977.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CASP10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 19 of the CASP10 protein (p.Ser19Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	5.1
DANN	Benign	0.92
DEOGEN2	Benign	0.030	.;.;T;.;.;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.65	T;T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.81	L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.23	T;T;T;T;D;T;T
Sift4G	Benign	0.10	T;D;T;D;T;T;T
Polyphen		0.33	B;.;B;.;B;B;B
Vest4		0.095
MutPred		0.53		Loss of ubiquitination at K14 (P = 0.0283);Loss of ubiquitination at K14 (P = 0.0283);Loss of ubiquitination at K14 (P = 0.0283);Loss of ubiquitination at K14 (P = 0.0283);Loss of ubiquitination at K14 (P = 0.0283);Loss of ubiquitination at K14 (P = 0.0283);Loss of ubiquitination at K14 (P = 0.0283);
MVP		0.82
MPC		0.081
ClinPred		0.16	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.067

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: rs1259990832; hg19: chr2-202050557;