Genetic Variant CASP12:p.Asp193Asn (chr11-104891260-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000375726.6(CASP12):c.577G>A(p.Asp193Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,536,382 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0092 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 50 hom. )

Consequence

CASP12
ENST00000375726.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.359

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003557533).

BP6

Variant 11-104891260-C-T is Benign according to our data. Variant chr11-104891260-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056983.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00918 (1395/151946) while in subpopulation AFR AF = 0.0285 (1183/41464). AF 95% confidence interval is 0.0272. There are 17 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

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.623G>A	non_coding_transcript_exon	Exon 4 of 8
CASP12	NR_034063.4	n.623G>A	non_coding_transcript_exon	Exon 4 of 7
CASP12	NR_034064.4	n.623G>A	non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP12	ENST00000375726.6	TSL:1	c.577G>A	p.Asp193Asn	missense	Exon 4 of 7	ENSP00000424038.1
CASP12	ENST00000613512.4	TSL:1	c.577G>A	p.Asp193Asn	missense	Exon 4 of 8	ENSP00000482745.1
CASP12	ENST00000441710.5	TSL:1	c.577G>A	p.Asp193Asn	missense	Exon 4 of 6	ENSP00000423970.1

Frequencies

GnomAD3 genomes

AF:

0.00916

AC:

1390

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00519

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00136

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00443

AC:

633

AN:

142780

AF XY:

0.00487

show subpopulations

Gnomad AFR exome

AF:

0.0302

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000240

Gnomad OTH exome

AF:

0.00209

GnomAD4 exome

AF:

0.00185

AC:

2558

AN:

1384436

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1507

AN XY:

683188

show subpopulations

African (AFR)

AF:

0.0304

AC:

958

AN:

31552

American (AMR)

AF:

0.00154

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25142

East Asian (EAS)

AF:

0.000727

AC:

AN:

35770

South Asian (SAS)

AF:

0.0157

AC:

1247

AN:

79238

European-Finnish (FIN)

AF:

0.0000287

AC:

AN:

34868

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1078560

Other (OTH)

AF:

0.00333

AC:

193

AN:

57918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

153

305

458

610

763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00918

AC:

1395

AN:

151946

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

680

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.0285

AC:

1183

AN:

41464

American (AMR)

AF:

0.00518

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00137

AC:

AN:

5128

South Asian (SAS)

AF:

0.0204

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67906

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00744

Hom.:

Bravo

AF:

0.00964

ExAC

AF:

0.00217

AC:

166

ClinVar

ClinVar submissions

Significance: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

0.14

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.9

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

PhyloP100

-0.36

PrimateAI

Benign

0.34

REVEL

Benign

0.061

Vest4

0.20

MVP

0.11

MPC

0.031

ClinPred

0.0065

GERP RS

3.1

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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