11-104891194-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000375726.6(CASP12):c.643A>G(p.Ile215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,536,496 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (50 hom.)
• Consequence: CASP12 ENST00000375726.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.450

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008485436).
• BP6: Variant 11-104891194-T-C is Benign according to our data. Variant chr11-104891194-T-C is described in ClinVar as [Benign]. Clinvar id is 3057055.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00922 (1402/152092) while in subpopulation AFR AF= 0.0285 (1183/41506). AF 95% confidence interval is 0.0272. There are 17 homozygotes in gnomad4. There are 680 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP12	NR_034068.4	n.227-671A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP12	ENST00000613512.4	c.643A>G	p.Ile215Val	missense_variant	4/8	1		P5

Frequencies

GnomAD3 genomes AF: 0.00919 AC: 1397 AN: 151974 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00512

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00443 AC: 638 AN: 144016 Hom.: 8 AF XY: 0.00489 AC XY: 377 AN XY: 77078

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00102

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00186 AC: 2571 AN: 1384404 Hom.: 50 Cov.: 32 AF XY: 0.00221 AC XY: 1513 AN XY: 683206

Gnomad4 AFR exome AF: 0.0303

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.000727

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000797

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00922 AC: 1402 AN: 152092 Hom.: 17 Cov.: 32 AF XY: 0.00915 AC XY: 680 AN XY: 74352

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.00511

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.000777 Hom.: 1

Bravo AF: 0.00967

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00211 AC: 172

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CASP12-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	9.4
Dann	Uncertain	1.0
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N;N
PrimateAI	Benign	0.31	T
REVEL	Benign	0.11
Vest4		0.31
MVP		0.067
MPC		0.054
ClinPred		0.040	T
GERP RS		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs115100183; hg19: chr11-104761921;