2-201209363-A-T

Variant names:

• chr2-201209363-A-T
• rs80358239
• NM_032977.4:c.1216A>T
• CASP10 p.Ile406Leu

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032977.4(CASP10):​c.1216A>T​(p.Ile406Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,130 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (35 hom.)
• Consequence: CASP10 NM_032977.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: -1.20
• Publications: 24 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006909907).
• BP6: Variant 2-201209363-A-T is Benign according to our data. Variant chr2-201209363-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 333435.
• BS2: High AC in GnomAd4 at 514 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.1216A>T	p.Ile406Leu	missense	Exon 9 of 10	NP_116759.2
	CASP10	NM_032974.5		c.1216A>T	p.Ile406Leu	missense	Exon 9 of 10	NP_116756.2
	CASP10	NM_001230.5		c.1087A>T	p.Ile363Leu	missense	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.1216A>T	p.Ile406Leu	missense	Exon 9 of 10	ENSP00000286186.6	Q92851-4
	CASP10	ENST00000448480.1	TSL:1	c.1087A>T	p.Ile363Leu	missense	Exon 7 of 8	ENSP00000396835.1	Q92851-5
	CASP10	ENST00000313728.12	TSL:1	c.1015A>T	p.Ile339Leu	missense	Exon 7 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152122 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00453 AC: 1136 AN: 251050 AF XY: 0.00532

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.00435

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00439 AC: 6418 AN: 1461890 Hom.: 35 Cov.: 35 AF XY: 0.00477 AC XY: 3466 AN XY: 727248

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

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

South Asian (SAS) AF: 0.0150 AC: 1290 AN: 86258

European-Finnish (FIN) AF: 0.00489 AC: 261 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00404 AC: 4490 AN: 1112012

Other (OTH) AF: 0.00386 AC: 233 AN: 60394

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152240 Hom.: 5 Cov.: 31 AF XY: 0.00337 AC XY: 251 AN XY: 74426

African (AFR) AF: 0.000409 AC: 17 AN: 41542

American (AMR) AF: 0.00144 AC: 22 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4808

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00523 AC: 356 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00351 Hom.: 3

Bravo AF: 0.00232

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Autoimmune lymphoproliferative syndrome type 2A (3)
-	-	1	Hypomyelination and Congenital Cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.5
DANN	Benign	0.84
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.39	N
PhyloP100		-1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.50	T
Varity_R		0.12
gMVP		0.23
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

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

Other links and lift over

dbSNP: rs80358239;

hg19: chr2-202074086;

COSMIC: COSV53777337;

COSMIC: COSV53777337;