dbSNP rs146027803: CASP12:p.Gly283Ser (chr11-104887276-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The ENST00000375726.6(CASP12):c.847G>A(p.Gly283Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,512,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CASP12
ENST00000375726.6 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.09

Publications

0 publications found

Variant links:

Genes affected

CASP12 (HGNC:19004): (caspase 12 (gene/pseudogene)) Caspases are cysteine proteases that cleave C-terminal aspartic acid residues on their substrate molecules. This gene is most highly related to members of the ICE subfamily of caspases that process inflammatory cytokines. In rodents, the homolog of this gene mediates apoptosis in response to endoplasmic reticulum stress. However, in humans this gene contains a polymorphism for the presence or absence of a premature stop codon. The majority of human individuals have the premature stop codon and produce a truncated non-functional protein. The read-through codon occurs primarily in individuals of African descent and carriers have endotoxin hypo-responsiveness and an increased susceptibility to severe sepsis. Several alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Feb 2011]

CASP12 links:

ENSG00000303891 (HGNC:):

ENSG00000303891 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033200294).

BP6

Variant 11-104887276-C-T is Benign according to our data. Variant chr11-104887276-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3035908.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375726.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank
CASP12	NR_034061.4	n.893G>A	non_coding_transcript_exon	Exon 6 of 8
CASP12	NR_034065.4	n.658G>A	non_coding_transcript_exon	Exon 5 of 7
CASP12	NR_034066.4	n.406G>A	non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP12	ENST00000375726.6	TSL:1	c.847G>A	p.Gly283Ser	missense	Exon 6 of 7	ENSP00000424038.1
CASP12	ENST00000613512.4	TSL:1	c.847G>A	p.Gly283Ser	missense	Exon 6 of 8	ENSP00000482745.1
CASP12	ENST00000448103.5	TSL:1	c.612G>A	p.Met204Ile	missense	Exon 5 of 6	ENSP00000423899.1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

191

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000300

AC:

AN:

126540

AF XY:

0.000262

show subpopulations

Gnomad AFR exome

AF:

0.00514

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

157

AN:

1360664

Hom.:

Cov.:

AF XY:

0.0000938

AC XY:

AN XY:

671918

show subpopulations

African (AFR)

AF:

0.00369

AC:

112

AN:

30386

American (AMR)

AF:

0.000407

AC:

AN:

31978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24694

East Asian (EAS)

AF:

0.000113

AC:

AN:

35392

South Asian (SAS)

AF:

0.0000396

AC:

AN:

75830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

9.38e-7

AC:

AN:

1065942

Other (OTH)

AF:

0.000420

AC:

AN:

57102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152008

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.00434

AC:

180

AN:

41510

American (AMR)

AF:

0.000525

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67918

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000738

Hom.:

Bravo

AF:

0.00149

ExAC

AF:

0.000225

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CASP12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.10

Eigen_PC

Benign

-0.039

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.036

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.29

PhyloP100

3.1

PrimateAI

Benign

0.44

REVEL

Uncertain

0.30

Vest4

0.75

MVP

0.067

MPC

0.15

ClinPred

0.20

GERP RS

4.3

Mutation Taster

=76/24

polymorphism

(source)

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

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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