rs764136136

Variant names:

• chr11-104891322-T-C
• rs764136136
• ENST00000375726.6:c.515A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-104891322-T-C
• chr11-104891322-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000375726.6(CASP12):​c.515A>G​(p.His172Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,535,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H172Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CASP12 ENST00000375726.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

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.561A>G		non_coding_transcript_exon	Exon 4 of 8
	CASP12	NR_034063.4		n.561A>G		non_coding_transcript_exon	Exon 4 of 7
	CASP12	NR_034064.4		n.561A>G		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.515A>G	p.His172Arg	missense	Exon 4 of 7	ENSP00000424038.1
	CASP12	ENST00000613512.4	TSL:1	c.515A>G	p.His172Arg	missense	Exon 4 of 8	ENSP00000482745.1
	CASP12	ENST00000441710.5	TSL:1	c.515A>G	p.His172Arg	missense	Exon 4 of 6	ENSP00000423970.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000495 AC: 7 AN: 141276 AF XY: 0.0000395

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 182 AN: 1383864 Hom.: 0 Cov.: 32 AF XY: 0.000129 AC XY: 88 AN XY: 682934

African (AFR) AF: 0.0000317 AC: 1 AN: 31528

American (AMR) AF: 0.0000560 AC: 2 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.00 AC: 0 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.000161 AC: 174 AN: 1078372

Other (OTH) AF: 0.0000864 AC: 5 AN: 57870

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74226

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.000131 AC: 2 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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: 0.000191 AC: 13 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000186 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.38	T
PhyloP100		5.5
PrimateAI	Uncertain	0.51	T
REVEL	Uncertain	0.40
Vest4		0.90
MVP		0.085
MPC		0.15
ClinPred		0.96	D
GERP RS		4.4
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764136136; hg19: chr11-104762049;