2-201186133-G-T

Variant names:

• chr2-201186133-G-T
• rs7608787
• NM_032977.4:c.347+9G>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.347+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,602,776 control chromosomes in the GnomAD database, including 1,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (979 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (867 hom.)
• Consequence: CASP10 NM_032977.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.118
• Publications: 2 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=-0.87).
• BP6: Variant 2-201186133-G-T is Benign according to our data. Variant chr2-201186133-G-T is described in ClinVar as Benign. ClinVar VariationId is 333420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 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.347+9G>T		intron	N/A	NP_116759.2
	CASP10	NM_032974.5		c.347+9G>T		intron	N/A	NP_116756.2
	CASP10	NM_001230.5		c.347+9G>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.347+9G>T		intron	N/A	ENSP00000286186.6
	CASP10	ENST00000448480.1	TSL:1	c.347+9G>T		intron	N/A	ENSP00000396835.1
	CASP10	ENST00000313728.12	TSL:1	c.347+9G>T		intron	N/A	ENSP00000314599.7

Frequencies

GnomAD3 genomes AF: 0.0625 AC: 9500 AN: 152068 Hom.: 977 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0463

GnomAD2 exomes AF: 0.0161 AC: 3924 AN: 243634 AF XY: 0.0123

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.00973

GnomAD4 exome AF: 0.00629 AC: 9126 AN: 1450590 Hom.: 867 Cov.: 27 AF XY: 0.00538 AC XY: 3888 AN XY: 722012

African (AFR) AF: 0.218 AC: 7234 AN: 33204

American (AMR) AF: 0.0134 AC: 597 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000663 AC: 57 AN: 85922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00892 AC: 37 AN: 4146

European-Non Finnish (NFE) AF: 0.000322 AC: 355 AN: 1103986

Other (OTH) AF: 0.0141 AC: 846 AN: 59906

GnomAD4 genome AF: 0.0626 AC: 9527 AN: 152186 Hom.: 979 Cov.: 32 AF XY: 0.0603 AC XY: 4489 AN XY: 74416

African (AFR) AF: 0.217 AC: 9002 AN: 41460

American (AMR) AF: 0.0238 AC: 364 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68014

Other (OTH) AF: 0.0458 AC: 97 AN: 2116

Alfa AF: 0.0319 Hom.: 211

Bravo AF: 0.0708

Asia WGS AF: 0.0110 AC: 38 AN: 3478

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	-0.87
CADD	Benign	0.88
DANN	Benign	0.69
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs7608787; hg19: chr2-202050856;