chr2-201208250-A-G

Variant names:

• chr2-201208250-A-G
• rs41419046
• NM_032977.4:c.922+67A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_032977.4(CASP10):​c.922+67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CASP10 NM_032977.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• 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), G2P
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS2: High AC in GnomAdExome4 at 5 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4	c.922+67A>G		intron_variant	Intron 8 of 9	ENST00000286186.11	NP_116759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11	c.922+67A>G		intron_variant	Intron 8 of 9	1	NM_032977.4	ENSP00000286186.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399632 Hom.: 0 Cov.: 30 AF XY: 0.00000289 AC XY: 2 AN XY: 692136

African (AFR) AF: 0.00 AC: 0 AN: 31028

American (AMR) AF: 0.00 AC: 0 AN: 33636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23620

East Asian (EAS) AF: 0.00 AC: 0 AN: 38048

South Asian (SAS) AF: 0.00 AC: 0 AN: 77232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00000462 AC: 5 AN: 1082922

Other (OTH) AF: 0.00 AC: 0 AN: 57888

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.45
DANN	Benign	0.78
PhyloP100		-0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41419046; hg19: chr2-202072973;