chr2-201209067-C-T

Variant names:

• chr2-201209067-C-T
• rs6753900
• NM_032977.4:c.923-3C>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.923-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0123 in 1,372,936 control chromosomes in the GnomAD database, including 1,590 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (854 hom., cov: 29)
  • Exomes 𝑓: 0.0065 (736 hom.)
• Consequence: CASP10 NM_032977.4 splice_region, intron
• Scores: Splicing: ADA: 0.001292
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.70
• Publications: 7 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: AD, Unknown Classification: STRONG, LIMITED Submitted by: ClinGen, 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=-0.61).
• BP6: Variant 2-201209067-C-T is Benign according to our data. Variant chr2-201209067-C-T is described in ClinVar as Benign. ClinVar VariationId is 333434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP10	NM_032977.4	MANE Select	c.923-3C>T		splice_region intron	N/A	NP_116759.2
	CASP10	NM_032974.5		c.923-3C>T		splice_region intron	N/A	NP_116756.2
	CASP10	NM_001230.5		c.794-3C>T		splice_region intron	N/A	NP_001221.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP10	ENST00000286186.11	TSL:1 MANE Select	c.923-3C>T		splice_region intron	N/A	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.794-3C>T		splice_region intron	N/A	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.722-3C>T		splice_region intron	N/A	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 8754 AN: 136290 Hom.: 852 Cov.: 29

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00725

Gnomad NFE AF: 0.000847

Gnomad OTH AF: 0.0495

GnomAD2 exomes AF: 0.0163 AC: 3610 AN: 221166 AF XY: 0.0123

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.00836

GnomAD4 exome AF: 0.00650 AC: 8043 AN: 1236566 Hom.: 736 Cov.: 34 AF XY: 0.00564 AC XY: 3506 AN XY: 621934

African (AFR) AF: 0.217 AC: 6361 AN: 29294

American (AMR) AF: 0.0118 AC: 454 AN: 38612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23116

East Asian (EAS) AF: 0.00 AC: 0 AN: 36782

South Asian (SAS) AF: 0.000677 AC: 53 AN: 78332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49498

Middle Eastern (MID) AF: 0.0117 AC: 45 AN: 3852

European-Non Finnish (NFE) AF: 0.000390 AC: 361 AN: 925254

Other (OTH) AF: 0.0148 AC: 769 AN: 51826

GnomAD4 genome AF: 0.0644 AC: 8776 AN: 136370 Hom.: 854 Cov.: 29 AF XY: 0.0639 AC XY: 4153 AN XY: 65006

African (AFR) AF: 0.219 AC: 8272 AN: 37714

American (AMR) AF: 0.0276 AC: 349 AN: 12638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4518

South Asian (SAS) AF: 0.00166 AC: 7 AN: 4220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7244

Middle Eastern (MID) AF: 0.00781 AC: 2 AN: 256

European-Non Finnish (NFE) AF: 0.000847 AC: 54 AN: 63722

Other (OTH) AF: 0.0490 AC: 92 AN: 1878

Alfa AF: 0.0228 Hom.: 370

Bravo AF: 0.0681

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autoimmune lymphoproliferative syndrome type 2A (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.9
DANN	Benign	0.62
PhyloP100		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.060		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: rs6753900; hg19: chr2-202073790;