chr11-104892390-A-G

Variant names:

• chr11-104892390-A-G
• rs497116
• ENST00000375726.6:c.373T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4 BA1

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
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -1.81
• Publications: 43 publications found

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]

ENSG00000303891 (HGNC:):

ACMG classification

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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP12	NR_034061.4		n.419T>C		non_coding_transcript_exon	Exon 3 of 8
	CASP12	NR_034063.4		n.419T>C		non_coding_transcript_exon	Exon 3 of 7
	CASP12	NR_034064.4		n.419T>C		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP12	ENST00000375726.6	TSL:1	c.373T>C	p.Ter125Argext*?	stop_lost	Exon 3 of 7	ENSP00000424038.1
	CASP12	ENST00000613512.4	TSL:1	c.373T>C	p.Ter125Argext*?	stop_lost	Exon 3 of 8	ENSP00000482745.1
	CASP12	ENST00000441710.5	TSL:1	c.373T>C	p.Ter125Argext*?	stop_lost	Exon 3 of 6	ENSP00000423970.1

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

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: 3 AN: 25112

East Asian (EAS) AF: 0.000728 AC: 26 AN: 35716

South Asian (SAS) AF: 0.0162 AC: 1279 AN: 79176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33894

Middle Eastern (MID) AF: 0.0102 AC: 58 AN: 5684

European-Non Finnish (NFE) AF: 0.000384 AC: 414 AN: 1077926

Other (OTH) AF: 0.0125 AC: 721 AN: 57814

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

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: 0 AN: 3472

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5146

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000648 AC: 44 AN: 67938

Other (OTH) AF: 0.0355 AC: 75 AN: 2110

Alfa AF: 0.0160 Hom.: 326

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

May 06, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.35
PhyloP100		-1.8

Splicing

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

Other links and lift over

dbSNP: rs497116; hg19: chr11-104763117;