rs12693932

Variant names:

• chr2-201228672-T-C
• rs12693932
• ENST00000448480.1:c.1287-261T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000448480.1(CASP10):​c.1287-261T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 152,044 control chromosomes in the GnomAD database, including 23,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (23149 hom., cov: 32)
• Consequence: CASP10 ENST00000448480.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.309
• Publications: 26 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-201228672-T-C is Benign according to our data. Variant chr2-201228672-T-C is described in ClinVar as [Benign]. Clinvar id is 1283306.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032974.5	c.1416-261T>C		intron_variant	Intron 9 of 9		NP_116756.2
CASP10	NM_001206542.2	c.1287-261T>C		intron_variant	Intron 7 of 7		NP_001193471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000448480.1	c.1287-261T>C		intron_variant	Intron 7 of 7	1		ENSP00000396835.1
CASP10	ENST00000272879.9	c.1416-261T>C		intron_variant	Intron 9 of 9	2		ENSP00000272879.5
CASP10	ENST00000696199.1	c.722-258T>C		intron_variant	Intron 6 of 6			ENSP00000512481.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82131 AN: 151926 Hom.: 23107 Cov.: 32

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.519

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.541 AC: 82229 AN: 152044 Hom.: 23149 Cov.: 32 AF XY: 0.532 AC XY: 39546 AN XY: 74334

African (AFR) AF: 0.680 AC: 28184 AN: 41452

American (AMR) AF: 0.445 AC: 6806 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1823 AN: 3466

East Asian (EAS) AF: 0.222 AC: 1150 AN: 5190

South Asian (SAS) AF: 0.319 AC: 1538 AN: 4820

European-Finnish (FIN) AF: 0.517 AC: 5455 AN: 10560

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35661 AN: 67968

Other (OTH) AF: 0.525 AC: 1106 AN: 2106

Alfa AF: 0.521 Hom.: 38038

Bravo AF: 0.541

Asia WGS AF: 0.302 AC: 1052 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12693932; hg19: chr2-202093395;