Genetic Variant NM_032977.4:c.177A>G (chr2-201185954-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032977.4(CASP10):c.177A>G(p.Ser59Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,588 control chromosomes in the GnomAD database, including 203,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18041 hom., cov: 31)

Exomes 𝑓: 0.50 ( 185337 hom. )

Consequence

CASP10
NM_032977.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.715

Publications

40 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), ClinGen, 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 2-201185954-A-G is Benign according to our data. Variant chr2-201185954-A-G is described in ClinVar as Benign. ClinVar VariationId is 333418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.715 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP10	NM_032977.4	MANE Select	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 10	NP_116759.2
CASP10	NM_032974.5		c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 10	NP_116756.2
CASP10	NM_001230.5		c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 8	NP_001221.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP10	ENST00000286186.11	TSL:1 MANE Select	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 10	ENSP00000286186.6	Q92851-4
CASP10	ENST00000448480.1	TSL:1	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 8	ENSP00000396835.1	Q92851-5
CASP10	ENST00000313728.12	TSL:1	c.177A>G	p.Ser59Ser	synonymous	Exon 2 of 8	ENSP00000314599.7	Q92851-6

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73309

AN:

151912

Hom.:

18023

Cov.:

show subpopulations

Gnomad AFR

AF:

0.484

Gnomad AMI

AF:

0.420

Gnomad AMR

AF:

0.418

Gnomad ASJ

AF:

0.526

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.522

Gnomad OTH

AF:

0.465

GnomAD2 exomes

AF:

0.448

AC:

112498

AN:

250972

AF XY:

0.448

show subpopulations

Gnomad AFR exome

AF:

0.483

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.226

Gnomad FIN exome

AF:

0.500

Gnomad NFE exome

AF:

0.519

Gnomad OTH exome

AF:

0.466

GnomAD4 exome

AF:

0.498

AC:

727762

AN:

1461558

Hom.:

185337

Cov.:

AF XY:

0.494

AC XY:

359307

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.486

AC:

16265

AN:

33474

American (AMR)

AF:

0.360

AC:

16091

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.522

AC:

13649

AN:

26136

East Asian (EAS)

AF:

0.197

AC:

7821

AN:

39700

South Asian (SAS)

AF:

0.355

AC:

30575

AN:

86248

European-Finnish (FIN)

AF:

0.499

AC:

26658

AN:

53396

Middle Eastern (MID)

AF:

0.410

AC:

2346

AN:

5728

European-Non Finnish (NFE)

AF:

0.526

AC:

585201

AN:

1111786

Other (OTH)

AF:

0.483

AC:

29156

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

20890

41780

62671

83561

104451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16546

33092

49638

66184

82730

<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

AF:

0.483

AC:

73370

AN:

152030

Hom.:

18041

Cov.:

AF XY:

0.476

AC XY:

35338

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.484

AC:

20057

AN:

41452

American (AMR)

AF:

0.417

AC:

6379

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

1822

AN:

3464

East Asian (EAS)

AF:

0.222

AC:

1150

AN:

5180

South Asian (SAS)

AF:

0.334

AC:

1605

AN:

4810

European-Finnish (FIN)

AF:

0.511

AC:

5397

AN:

10558

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.522

AC:

35471

AN:

67968

Other (OTH)

AF:

0.472

AC:

994

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1940

3881

5821

7762

9702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.504

Hom.:

60411

Bravo

AF:

0.474

Asia WGS

AF:

0.301

AC:

1048

AN:

3478

EpiCase

AF:

0.506

EpiControl

AF:

0.516

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Autoimmune lymphoproliferative syndrome type 2A (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.78

(source)

DANN

Benign

0.50

PhyloP100

-0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over