chr2-201209484-A-G

Position:

• chr2-201209484-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032977.4(CASP10):​c.1337A>G​(p.Tyr446Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,613,824 control chromosomes in the GnomAD database, including 1,305 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (80 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1225 hom.)
• Consequence: CASP10 NM_032977.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.111

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032116473).
• BP6: Variant 2-201209484-A-G is Benign according to our data. Variant chr2-201209484-A-G is described in ClinVar as [Benign]. Clinvar id is 21728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201209484-A-G is described in Lovd as [Likely_benign]. Variant chr2-201209484-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0282 (4295/152284) while in subpopulation NFE AF= 0.0405 (2758/68018). AF 95% confidence interval is 0.0393. There are 80 homozygotes in gnomad4. There are 2096 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4295 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP10	NM_032977.4	c.1337A>G	p.Tyr446Cys	missense_variant	9/10	ENST00000286186.11	NP_116759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11	c.1337A>G	p.Tyr446Cys	missense_variant	9/10	1	NM_032977.4	ENSP00000286186.6

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4295 AN: 152166 Hom.: 80 Cov.: 31

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0296 AC: 7429 AN: 250904 Hom.: 163 AF XY: 0.0288 AC XY: 3909 AN XY: 135590

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00778

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0371 AC: 54164 AN: 1461540 Hom.: 1225 Cov.: 35 AF XY: 0.0364 AC XY: 26450 AN XY: 727072

Gnomad4 AFR exome AF: 0.00589

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00820

Gnomad4 FIN exome AF: 0.0662

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0306

GnomAD4 genome AF: 0.0282 AC: 4295 AN: 152284 Hom.: 80 Cov.: 31 AF XY: 0.0282 AC XY: 2096 AN XY: 74456

Gnomad4 AFR AF: 0.00647

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00602

Gnomad4 FIN AF: 0.0632

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0365 Hom.: 60

Bravo AF: 0.0245

TwinsUK AF: 0.0413 AC: 153

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0374 AC: 322

ExAC AF: 0.0294 AC: 3574

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0367

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2A Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	This variant is associated with the following publications: (PMID: 31309545, 16537120, 26323380, 16446975, 17999750) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.6
DANN	Benign	0.67
DEOGEN2	Benign	0.13	.;T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0032	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Benign	0.068
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.73	P;P;P;P;B
Vest4		0.061
MPC		0.22
ClinPred		0.050	T
GERP RS		1.0
Varity_R		0.25
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs17860405; hg19: chr2-202074207;