chr11-104891301-C-A

Variant names:

• chr11-104891301-C-A
• rs980868478
• ENST00000375726.6:c.536G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000375726.6(CASP12):​c.536G>T​(p.Cys179Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000977 in 1,535,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C179Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: CASP12 ENST00000375726.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3806055).

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.582G>T		non_coding_transcript_exon	Exon 4 of 8
	CASP12	NR_034063.4		n.582G>T		non_coding_transcript_exon	Exon 4 of 7
	CASP12	NR_034064.4		n.582G>T		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.536G>T	p.Cys179Phe	missense	Exon 4 of 7	ENSP00000424038.1
	CASP12	ENST00000613512.4	TSL:1	c.536G>T	p.Cys179Phe	missense	Exon 4 of 8	ENSP00000482745.1
	CASP12	ENST00000441710.5	TSL:1	c.536G>T	p.Cys179Phe	missense	Exon 4 of 6	ENSP00000423970.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000795 AC: 11 AN: 1383988 Hom.: 0 Cov.: 32 AF XY: 0.00000732 AC XY: 5 AN XY: 682986

African (AFR) AF: 0.00 AC: 0 AN: 31530

American (AMR) AF: 0.00 AC: 0 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000927 AC: 10 AN: 1078428

Other (OTH) AF: 0.0000173 AC: 1 AN: 57880

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151958 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.0000657 AC: 1 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.21
Vest4		0.48
MVP		0.21
MPC		0.055
ClinPred		0.95	D
GERP RS		4.4
Mutation Taster		=77/23	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: rs980868478; hg19: chr11-104762028;