chr2-201187780-C-G

Variant names:

• chr2-201187780-C-G
• rs780552445
• NM_032977.4:c.422C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032977.4(CASP10):​c.422C>G​(p.Ser141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S141L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASP10 NM_032977.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 publications found

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]

CASP10 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2A

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3779993).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032977.4. 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
	CASP10	NM_032977.4	MANE Select	c.422C>G	p.Ser141Trp	missense	Exon 3 of 10	NP_116759.2
	CASP10	NM_032974.5		c.422C>G	p.Ser141Trp	missense	Exon 3 of 10	NP_116756.2
	CASP10	NM_001230.5		c.422C>G	p.Ser141Trp	missense	Exon 3 of 8	NP_001221.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP10	ENST00000286186.11	TSL:1 MANE Select	c.422C>G	p.Ser141Trp	missense	Exon 3 of 10	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.422C>G	p.Ser141Trp	missense	Exon 3 of 8	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.422C>G	p.Ser141Trp	missense	Exon 3 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461460 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111646

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.7
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.015	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-1.2
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.074
Sift	Benign	0.030	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.53		Loss of disorder (P = 9e-04)
MVP		0.60
MPC		0.43
ClinPred		0.89	D
GERP RS		-3.1
Varity_R		0.29
gMVP		0.25
Mutation Taster		=89/11	polymorphism

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: rs780552445; hg19: chr2-202052503;