Genetic Variant CASP10:c.923-3C>A (chr2-201209067-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_032977.4(CASP10):c.923-3C>A variant causes a splice region, intron change. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CASP10
NM_032977.4 splice_region, intron

Scores

Splicing: ADA: 0.9920

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70

Publications

7 publications found

Variant links:

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

CASP10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP10	NM_032977.4 link	c.923-3C>A		splice_region_variant, intron_variant	Intron 8 of 9	ENST00000286186.11	NP_116759.2	Q92851-4A0A0S2Z3Z5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP10	ENST00000286186.11 link	c.923-3C>A		splice_region_variant, intron_variant	Intron 8 of 9	1	NM_032977.4	ENSP00000286186.6		Q92851-4

Frequencies

GnomAD3 genomes

AF:

0.0000734

AC:

AN:

136274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000238

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000442

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000276

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000314

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000407

AC:

AN:

221166

AF XY:

0.0000498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000333

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000107

Gnomad NFE exome

AF:

0.0000603

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00102

AC:

1248

AN:

1227302

Hom.:

Cov.:

AF XY:

0.000942

AC XY:

582

AN XY:

617578

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000478

AC:

AN:

29300

American (AMR)

AF:

0.000311

AC:

AN:

38534

Ashkenazi Jewish (ASJ)

AF:

0.000740

AC:

AN:

22988

East Asian (EAS)

AF:

0.000356

AC:

AN:

36560

South Asian (SAS)

AF:

0.000243

AC:

AN:

78100

European-Finnish (FIN)

AF:

0.000792

AC:

AN:

49242

Middle Eastern (MID)

AF:

0.00263

AC:

AN:

3808

European-Non Finnish (NFE)

AF:

0.00118

AC:

1080

AN:

917342

Other (OTH)

AF:

0.000856

AC:

AN:

51428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.240

Heterozygous variant carriers

208

416

624

832

1040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000733

AC:

AN:

136354

Hom.:

Cov.:

AF XY:

0.0000769

AC XY:

AN XY:

64998

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000265

AC:

AN:

37760

American (AMR)

AF:

0.000237

AC:

AN:

12634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3320

East Asian (EAS)

AF:

0.000443

AC:

AN:

4516

South Asian (SAS)

AF:

0.00

AC:

AN:

4212

European-Finnish (FIN)

AF:

0.000276

AC:

AN:

7234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.0000314

AC:

AN:

63686

Other (OTH)

AF:

0.00

AC:

AN:

1878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.235

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000269

Hom.:

370

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

See cases

Uncertain:1

Dec 03, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

3.7

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 5

DS_AL_spliceai

0.29

Position offset: 3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over