dbSNP rs497116: CASP12:p.Ter125Argext*? (chr11-104892390-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4BA1

The ENST00000375726.6(CASP12):c.373T>C(p.Ter125Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00872 in 1,534,558 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.041 ( 415 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 361 hom. )

Consequence

CASP12
ENST00000375726.6 stop_lost

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: -1.81

Publications

43 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 -6 ACMG points.

PM4

Stoplost variant in ENST00000375726.6 Downstream stopcodon found after 61 codons.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
CASP12	NR_034061.4 link	n.419T>C	non_coding_transcript_exon_variant	Exon 3 of 8
CASP12	NR_034063.4 link	n.419T>C	non_coding_transcript_exon_variant	Exon 3 of 7
CASP12	NR_034064.4 link	n.419T>C	non_coding_transcript_exon_variant	Exon 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP12	ENST00000375726.6 link	c.373T>C	p.Ter125Argext*?	stop_lost	Exon 3 of 7	1		ENSP00000424038.1

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6181

AN:

151944

Hom.:

405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00136

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000648

Gnomad OTH

AF:

0.0359

GnomAD4 exome

AF:

0.00518

AC:

7163

AN:

1382496

Hom.:

361

Cov.:

AF XY:

0.00514

AC XY:

3506

AN XY:

682194

show subpopulations

African (AFR)

AF:

0.136

AC:

4269

AN:

31498

American (AMR)

AF:

0.0110

AC:

393

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.000119

AC:

AN:

25112

East Asian (EAS)

AF:

0.000728

AC:

AN:

35716

South Asian (SAS)

AF:

0.0162

AC:

1279

AN:

79176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33894

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.000384

AC:

414

AN:

1077926

Other (OTH)

AF:

0.0125

AC:

721

AN:

57814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

378

756

1134

1512

1890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<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:

0.0409

AC:

6225

AN:

152062

Hom.:

415

Cov.:

AF XY:

0.0404

AC XY:

3002

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.136

AC:

5657

AN:

41498

American (AMR)

AF:

0.0219

AC:

334

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00136

AC:

AN:

5146

South Asian (SAS)

AF:

0.0213

AC:

103

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000648

AC:

AN:

67938

Other (OTH)

AF:

0.0355

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

261

523

784

1046

1307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0160

Hom.:

326

Bravo

AF:

0.0457

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Sepsis, susceptibility to

Other:1

May 06, 2004

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.35

(source)

PhyloP100

-1.8

Splicing

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