2-201209215-G-T

Variant names:

• chr2-201209215-G-T
• rs111489269
• NM_032977.4:c.1068G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032977.4(CASP10):​c.1068G>T​(p.Leu356Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000869 in 1,614,062 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L356L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (11 hom.)
• Consequence: CASP10 NM_032977.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.858
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-201209215-G-T is Benign according to our data. Variant chr2-201209215-G-T is described in ClinVar as Benign. ClinVar VariationId is 535763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 643 AD,Unknown 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.1068G>T	p.Leu356Leu	synonymous	Exon 9 of 10	NP_116759.2
	CASP10	NM_032974.5		c.1068G>T	p.Leu356Leu	synonymous	Exon 9 of 10	NP_116756.2
	CASP10	NM_001230.5		c.939G>T	p.Leu313Leu	synonymous	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.1068G>T	p.Leu356Leu	synonymous	Exon 9 of 10	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.939G>T	p.Leu313Leu	synonymous	Exon 7 of 8	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.867G>T	p.Leu289Leu	synonymous	Exon 7 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152096 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00118 AC: 296 AN: 251214 AF XY: 0.000832

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000520 AC: 760 AN: 1461850 Hom.: 11 Cov.: 35 AF XY: 0.000455 AC XY: 331 AN XY: 727228

African (AFR) AF: 0.0158 AC: 529 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111984

Other (OTH) AF: 0.00215 AC: 130 AN: 60388

GnomAD4 genome AF: 0.00422 AC: 643 AN: 152212 Hom.: 3 Cov.: 31 AF XY: 0.00404 AC XY: 301 AN XY: 74428

African (AFR) AF: 0.0145 AC: 600 AN: 41520

American (AMR) AF: 0.00183 AC: 28 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00278 Hom.: 0

Bravo AF: 0.00518

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoimmune lymphoproliferative syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.3
DANN	Benign	0.78
PhyloP100		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs111489269; hg19: chr2-202073938;