2-201208250-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_032977.4(CASP10):​c.922+67A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,551,694 control chromosomes in the GnomAD database, including 181 homozygotes. 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: 𝑓 0.011 (20 hom., cov: 32)
  • Exomes 𝑓: 0.012 (161 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: AD, Unknown Classification: STRONG, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0119 (16638/1399456) while in subpopulation SAS AF = 0.0169 (1308/77228). AF 95% confidence interval is 0.0162. There are 161 homozygotes in GnomAdExome4. There are 8432 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1685 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.922+67A>T		intron	N/A	NP_116759.2
	CASP10	NM_032974.5		c.922+67A>T		intron	N/A	NP_116756.2
	CASP10	NM_001230.5		c.793+67A>T		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.922+67A>T		intron	N/A	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.793+67A>T		intron	N/A	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.722-820A>T		intron	N/A	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1686 AN: 152120 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0537

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.0119 AC: 16638 AN: 1399456 Hom.: 161 Cov.: 30 AF XY: 0.0122 AC XY: 8432 AN XY: 692034

African (AFR) AF: 0.00129 AC: 40 AN: 31028

American (AMR) AF: 0.00416 AC: 140 AN: 33636

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 743 AN: 23616

East Asian (EAS) AF: 0.00118 AC: 45 AN: 38048

South Asian (SAS) AF: 0.0169 AC: 1308 AN: 77228

European-Finnish (FIN) AF: 0.0518 AC: 2577 AN: 49744

Middle Eastern (MID) AF: 0.00927 AC: 51 AN: 5504

European-Non Finnish (NFE) AF: 0.0102 AC: 11043 AN: 1082764

Other (OTH) AF: 0.0119 AC: 691 AN: 57888

GnomAD4 genome AF: 0.0111 AC: 1685 AN: 152238 Hom.: 20 Cov.: 32 AF XY: 0.0127 AC XY: 947 AN XY: 74426

African (AFR) AF: 0.00193 AC: 80 AN: 41554

American (AMR) AF: 0.00445 AC: 68 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0161 AC: 78 AN: 4830

European-Finnish (FIN) AF: 0.0537 AC: 568 AN: 10584

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 718 AN: 67998

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00570 Hom.: 0

Bravo AF: 0.00752

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.62
DANN	Benign	0.77
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41419046;

hg19: chr2-202072973;