ENST00000375726.6:c.639G>A

Variant names:

• chr11-104891198-C-T
• rs749654200
• ENST00000375726.6:c.639G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The ENST00000375726.6(CASP12):​c.639G>A​(p.Lys213Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,536,404 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: CASP12 ENST00000375726.6 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.383
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-104891198-C-T is Benign according to our data. Variant chr11-104891198-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3052992.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.383 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP12	NR_034061.4		n.685G>A		non_coding_transcript_exon	Exon 4 of 8
	CASP12	NR_034063.4		n.685G>A		non_coding_transcript_exon	Exon 4 of 7
	CASP12	NR_034064.4		n.685G>A		splice_region non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP12	ENST00000375726.6	TSL:1	c.639G>A	p.Lys213Lys	synonymous	Exon 4 of 7	ENSP00000424038.1
	CASP12	ENST00000613512.4	TSL:1	c.639G>A	p.Lys213Lys	synonymous	Exon 4 of 8	ENSP00000482745.1
	CASP12	ENST00000441710.5	TSL:1	c.639G>A	p.Lys213Lys	splice_region synonymous	Exon 4 of 6	ENSP00000423970.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151854 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000187 AC: 27 AN: 144174 AF XY: 0.000233

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000161 AC: 223 AN: 1384550 Hom.: 1 Cov.: 32 AF XY: 0.000181 AC XY: 124 AN XY: 683272

African (AFR) AF: 0.00 AC: 0 AN: 31544

American (AMR) AF: 0.000504 AC: 18 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35776

South Asian (SAS) AF: 0.000416 AC: 33 AN: 79246

European-Finnish (FIN) AF: 0.0000286 AC: 1 AN: 34972

Middle Eastern (MID) AF: 0.000704 AC: 4 AN: 5682

European-Non Finnish (NFE) AF: 0.000143 AC: 154 AN: 1078518

Other (OTH) AF: 0.000224 AC: 13 AN: 57986

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151854 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74150

African (AFR) AF: 0.0000242 AC: 1 AN: 41358

American (AMR) AF: 0.000525 AC: 8 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67900

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000272

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CASP12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.1
DANN	Benign	0.86
PhyloP100		-0.38
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs749654200; hg19: chr11-104761925;