rs11674246

Variant names:

• chr2-201183400-C-T
• rs11674246
• NM_032977.4:c.-8+92C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032977.4(CASP10):​c.-8+92C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 151,926 control chromosomes in the GnomAD database, including 13,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13665 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASP10 NM_032977.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.138
• Publications: 12 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), G2P
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-201183400-C-T is Benign according to our data. Variant chr2-201183400-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP10	NM_032977.4	MANE Select	c.-8+92C>T		intron	N/A	NP_116759.2
	CASP10	NM_032974.5		c.-8+92C>T		intron	N/A	NP_116756.2
	CASP10	NM_001230.5		c.-8+92C>T		intron	N/A	NP_001221.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP10	ENST00000286186.11	TSL:1 MANE Select	c.-8+92C>T		intron	N/A	ENSP00000286186.6
	CASP10	ENST00000448480.1	TSL:1	c.-8+92C>T		intron	N/A	ENSP00000396835.1
	CASP10	ENST00000313728.12	TSL:1	c.-8+92C>T		intron	N/A	ENSP00000314599.7

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63418 AN: 151808 Hom.: 13666 Cov.: 32

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.421

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.417 AC: 63425 AN: 151926 Hom.: 13665 Cov.: 32 AF XY: 0.412 AC XY: 30554 AN XY: 74228

African (AFR) AF: 0.349 AC: 14442 AN: 41416

American (AMR) AF: 0.384 AC: 5856 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1516 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1127 AN: 5176

South Asian (SAS) AF: 0.274 AC: 1320 AN: 4816

European-Finnish (FIN) AF: 0.480 AC: 5049 AN: 10512

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32766 AN: 67962

Other (OTH) AF: 0.420 AC: 885 AN: 2108

Alfa AF: 0.437 Hom.: 4931

Bravo AF: 0.410

Asia WGS AF: 0.240 AC: 837 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		0.14
PromoterAI		0.0081	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs11674246; hg19: chr2-202048123;