rs501192

Variant names:

• chr11-105029658-C-T
• rs501192
• NM_001257118.3:c.862+7G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 publications found

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]

ENSG00000303891 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CASP1	NM_001257118.3	c.862+7G>A		splice_region_variant, intron_variant	Intron 6 of 8	ENST00000533400.6	NP_001244047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP1	ENST00000533400.6	c.862+7G>A		splice_region_variant, intron_variant	Intron 6 of 8	1	NM_001257118.3	ENSP00000433138.1

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

GnomAD2 exomes AF: 0.172 AC: 42936 AN: 250150 AF XY: 0.165

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 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

African (AFR) AF: 0.0949 AC: 3142 AN: 33118

American (AMR) AF: 0.319 AC: 14202 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4375 AN: 25960

East Asian (EAS) AF: 0.00230 AC: 91 AN: 39598

South Asian (SAS) AF: 0.107 AC: 9219 AN: 85902

European-Finnish (FIN) AF: 0.217 AC: 11557 AN: 53348

Middle Eastern (MID) AF: 0.113 AC: 643 AN: 5704

European-Non Finnish (NFE) AF: 0.168 AC: 184773 AN: 1096816

Other (OTH) AF: 0.150 AC: 8972 AN: 59810

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

African (AFR) AF: 0.0980 AC: 4068 AN: 41504

American (AMR) AF: 0.246 AC: 3754 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3466

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5178

South Asian (SAS) AF: 0.112 AC: 539 AN: 4830

European-Finnish (FIN) AF: 0.217 AC: 2299 AN: 10584

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11314 AN: 67996

Other (OTH) AF: 0.160 AC: 337 AN: 2104

Alfa AF: 0.159 Hom.: 1536

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
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs501192; hg19: chr11-104900385; COSMIC: COSV62056372; COSMIC: COSV62056372;