rs497116

Positions:

• chr11-104892390-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BA1

The ENST00000375726.6(CASP12):​c.373T>C​(p.Ter125ArgextTer?) 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
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -1.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM4: Stoplost variant in ENST00000375726.6 Downstream stopcodon found after 32 codons.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP12	NR_034068.4	n.167T>C		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP12	ENST00000613512.4	c.373T>C	p.Ter125ArgextTer?	stop_lost	3/8	1		ENSP00000482745	P5

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6181 AN: 151944 Hom.: 405 Cov.: 32

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.: 31 AF XY: 0.00514 AC XY: 3506 AN XY: 682194

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.000728

Gnomad4 SAS exome AF: 0.0162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000384

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0409 AC: 6225 AN: 152062 Hom.: 415 Cov.: 32 AF XY: 0.0404 AC XY: 3002 AN XY: 74328

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000648

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.00752 Hom.: 99

Bravo AF: 0.0457

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Sepsis, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 06, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs497116; hg19: chr11-104763117;