rs780552445

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-201187780-C-A
• chr2-201187780-C-G
• chr2-201187780-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_032977.4(CASP10):​c.422C>A​(p.Ser141*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S141S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CASP10 NM_032977.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAdExome4 at 21 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.422C>A	p.Ser141*	stop_gained	Exon 3 of 10	NP_116759.2
	CASP10	NM_032974.5		c.422C>A	p.Ser141*	stop_gained	Exon 3 of 10	NP_116756.2
	CASP10	NM_001230.5		c.422C>A	p.Ser141*	stop_gained	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>A	p.Ser141*	stop_gained	Exon 3 of 10	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.422C>A	p.Ser141*	stop_gained	Exon 3 of 8	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.422C>A	p.Ser141*	stop_gained	Exon 3 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251348 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461458 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 727070

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: 0.000220 AC: 19 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: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Benign	0.92
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.0074	N
PhyloP100		-1.2
Vest4		0.52
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=81/119	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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;