Genetic Variant ENST00000375726.6:c.515A>C (chr11-104891322-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000375726.6(CASP12):c.515A>C(p.His172Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H172Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CASP12
ENST00000375726.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.46

Publications

0 publications found

Variant links:

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]

CASP12 links:

ENSG00000303891 (HGNC:):

ENSG00000303891 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

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

Gene	Transcript	HGVSc	Effect	Exon Rank
CASP12	NR_034061.4	n.561A>C	non_coding_transcript_exon	Exon 4 of 8
CASP12	NR_034063.4	n.561A>C	non_coding_transcript_exon	Exon 4 of 7
CASP12	NR_034064.4	n.561A>C	non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP12	ENST00000375726.6	TSL:1	c.515A>C	p.His172Pro	missense	Exon 4 of 7	ENSP00000424038.1
CASP12	ENST00000613512.4	TSL:1	c.515A>C	p.His172Pro	missense	Exon 4 of 8	ENSP00000482745.1
CASP12	ENST00000441710.5	TSL:1	c.515A>C	p.His172Pro	missense	Exon 4 of 6	ENSP00000423970.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.25

PhyloP100

5.5

PrimateAI

Benign

0.47

REVEL

Uncertain

0.53

Vest4

0.93

MVP

0.10

MPC

0.17

ClinPred

0.99

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over