rs501192

Positions:

• chr11-105029658-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001257118.3(CASP1):​c.862+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,596,892 control chromosomes in the GnomAD database, including 23,320 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2034 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21286 hom.)
• Consequence: CASP1 NM_001257118.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008079
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267

Genes affected

CASP1 (HGNC:1499): (caspase 1) This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce 2 subunits, large and small, that dimerize to form the active enzyme. This gene was identified by its ability to proteolytically cleave and activate the inactive precursor of interleukin-1, a cytokine involved in the processes such as inflammation, septic shock, and wound healing. This gene has been shown to induce cell apoptosis and may function in various developmental stages. Studies of a similar gene in mouse suggest a role in the pathogenesis of Huntington disease. Alternative splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

LOC124902742 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP1	NM_001257118.3	c.862+7G>A		splice_region_variant, intron_variant		ENST00000533400.6	NP_001244047.1
LOC124902742	XR_007062869.1	n.41-1689C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP1	ENST00000533400.6	c.862+7G>A		splice_region_variant, intron_variant		1	NM_001257118.3	ENSP00000433138	P2

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23174 AN: 152008 Hom.: 2030 Cov.: 32

Gnomad AFR AF: 0.0977

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.172 AC: 42936 AN: 250150 Hom.: 4625 AF XY: 0.165 AC XY: 22281 AN XY: 135288

Gnomad AFR exome AF: 0.0966

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.00463

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.164 AC: 236974 AN: 1444766 Hom.: 21286 Cov.: 29 AF XY: 0.161 AC XY: 116093 AN XY: 719930

Gnomad4 AFR exome AF: 0.0949

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.00230

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.153 AC: 23200 AN: 152126 Hom.: 2034 Cov.: 32 AF XY: 0.155 AC XY: 11540 AN XY: 74362

Gnomad4 AFR AF: 0.0980

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.160

Alfa AF: 0.159 Hom.: 1425

Bravo AF: 0.155

Asia WGS AF: 0.0760 AC: 262 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.2
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.0
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: rs501192; hg19: chr11-104900385; COSMIC: COSV62056372; COSMIC: COSV62056372;