NM_032977.4:c.1202_1208delGCCAAGG

Variant names:

• chr2-201209348-TGCCAAGG-T
• rs747900630
• NM_032977.4:c.1202_1208delGCCAAGG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_032977.4(CASP10):​c.1202_1208delGCCAAGG​(p.Cys401LeufsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,614,056 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: CASP10 NM_032977.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 10.0
• Publications: 2 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 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-201209348-TGCCAAGG-T is Benign according to our data. Variant chr2-201209348-TGCCAAGG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 535760.
• BS2: High AC in GnomAd4 at 47 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.1202_1208delGCCAAGG	p.Cys401LeufsTer15	frameshift	Exon 9 of 10	NP_116759.2
	CASP10	NM_032974.5		c.1202_1208delGCCAAGG	p.Cys401LeufsTer15	frameshift	Exon 9 of 10	NP_116756.2
	CASP10	NM_001230.5		c.1073_1079delGCCAAGG	p.Cys358LeufsTer15	frameshift	Exon 7 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.1202_1208delGCCAAGG	p.Cys401LeufsTer15	frameshift	Exon 9 of 10	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.1073_1079delGCCAAGG	p.Cys358LeufsTer15	frameshift	Exon 7 of 8	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.1001_1007delGCCAAGG	p.Cys334LeufsTer15	frameshift	Exon 7 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000367 AC: 92 AN: 250942 AF XY: 0.000324

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1461890 Hom.: 2 AF XY: 0.000325 AC XY: 236 AN XY: 727246

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000309 AC: 344 AN: 1112012

Other (OTH) AF: 0.000695 AC: 42 AN: 60394

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74330

African (AFR) AF: 0.000265 AC: 11 AN: 41436

American (AMR) AF: 0.000916 AC: 14 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68030

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000563

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Autoimmune lymphoproliferative syndrome type 1 (1)
-	1	-	Autoimmune lymphoproliferative syndrome type 2A (1)
-	1	-	CASP10-related disorder (1)
-	1	-	Gastric cancer;C1858968:Autoimmune lymphoproliferative syndrome type 2A;C4721532:Lymphoma, non-Hodgkin, familial (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=173/27	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747900630; hg19: chr2-202074071; COSMIC: COSV53777433; COSMIC: COSV53777433;