NM_032977.4:c.29C>G

Variant names:

• chr2-201185806-C-G
• rs1188335683
• NM_032977.4:c.29C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032977.4(CASP10):​c.29C>G​(p.Ser10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CASP10 NM_032977.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.125
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12829381).
• BS2: High AC in GnomAdExome4 at 11 Unknown,AD gene.

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.29C>G	p.Ser10Cys	missense	Exon 2 of 10	NP_116759.2
	CASP10	NM_032974.5		c.29C>G	p.Ser10Cys	missense	Exon 2 of 10	NP_116756.2
	CASP10	NM_001230.5		c.29C>G	p.Ser10Cys	missense	Exon 2 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.29C>G	p.Ser10Cys	missense	Exon 2 of 10	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.29C>G	p.Ser10Cys	missense	Exon 2 of 8	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.29C>G	p.Ser10Cys	missense	Exon 2 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251332 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461572 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727116

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autoimmune lymphoproliferative syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.13
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.069
Sift	Benign	0.038	D
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.22
MutPred		0.32		Loss of disorder (P = 0.001)
MVP		0.72
MPC		0.38
ClinPred		0.20	T
GERP RS		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.14
Mutation Taster		=98/2	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: rs1188335683; hg19: chr2-202050529;