rs200638628

Positions:

• chr2-201209570-C-G
• chr2-201209570-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032977.4(CASP10):​c.1415+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,597,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CASP10 NM_032977.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003080
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.67

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-201209570-C-G is Benign according to our data. Variant chr2-201209570-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 333439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201209570-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP10	NM_032977.4	c.1415+8C>G		splice_region_variant, intron_variant		ENST00000286186.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP10	ENST00000286186.11	c.1415+8C>G		splice_region_variant, intron_variant		1	NM_032977.4	P2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000102 AC: 24 AN: 234718 Hom.: 0 AF XY: 0.000118 AC XY: 15 AN XY: 127610

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.0000648

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000732

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.000536

GnomAD4 exome AF: 0.000124 AC: 179 AN: 1445558 Hom.: 0 Cov.: 34 AF XY: 0.000131 AC XY: 94 AN XY: 718864

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.0000490

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000971

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CASP10-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.22
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs200638628; hg19: chr2-202074293;