rs3731714

Variant names:

• chr2-201196097-C-T
• rs3731714
• NM_032977.4:c.684+149C>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.684+149C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 626,684 control chromosomes in the GnomAD database, including 23,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4558 hom., cov: 32)
  • Exomes 𝑓: 0.27 (18585 hom.)
• Consequence: CASP10 NM_032977.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.274
• Publications: 33 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=-0.79).
• BP6: Variant 2-201196097-C-T is Benign according to our data. Variant chr2-201196097-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4	c.684+149C>T		intron_variant	Intron 5 of 9	ENST00000286186.11	NP_116759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11	c.684+149C>T		intron_variant	Intron 5 of 9	1	NM_032977.4	ENSP00000286186.6

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33280 AN: 151912 Hom.: 4558 Cov.: 32

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.271 AC: 128455 AN: 474654 Hom.: 18585 AF XY: 0.267 AC XY: 67734 AN XY: 253298

African (AFR) AF: 0.0547 AC: 744 AN: 13606

American (AMR) AF: 0.226 AC: 4666 AN: 20672

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 3442 AN: 14024

East Asian (EAS) AF: 0.174 AC: 5775 AN: 33120

South Asian (SAS) AF: 0.225 AC: 11302 AN: 50190

European-Finnish (FIN) AF: 0.309 AC: 9914 AN: 32136

Middle Eastern (MID) AF: 0.209 AC: 410 AN: 1958

European-Non Finnish (NFE) AF: 0.302 AC: 85239 AN: 282226

Other (OTH) AF: 0.261 AC: 6963 AN: 26722

GnomAD4 genome AF: 0.219 AC: 33277 AN: 152030 Hom.: 4558 Cov.: 32 AF XY: 0.217 AC XY: 16098 AN XY: 74326

African (AFR) AF: 0.0551 AC: 2289 AN: 41508

American (AMR) AF: 0.231 AC: 3523 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3472

East Asian (EAS) AF: 0.184 AC: 951 AN: 5162

South Asian (SAS) AF: 0.218 AC: 1050 AN: 4816

European-Finnish (FIN) AF: 0.324 AC: 3417 AN: 10558

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.302 AC: 20487 AN: 67938

Other (OTH) AF: 0.229 AC: 480 AN: 2100

Alfa AF: 0.273 Hom.: 11439

Bravo AF: 0.207

Asia WGS AF: 0.177 AC: 616 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

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	-0.79
CADD	Benign	2.1
DANN	Benign	0.78
PhyloP100		-0.27
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: rs3731714; hg19: chr2-202060820;