rs580253

Positions:

• chr11-105029761-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001257118.3(CASP1):​c.766C>T​(p.Leu256Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,612,946 control chromosomes in the GnomAD database, including 23,608 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2029 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21579 hom.)
• Consequence: CASP1 NM_001257118.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.744

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=0.744 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP1	NM_001257118.3	c.766C>T	p.Leu256Leu	synonymous_variant	6/9	ENST00000533400.6	NP_001244047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP1	ENST00000533400.6	c.766C>T	p.Leu256Leu	synonymous_variant	6/9	1	NM_001257118.3	ENSP00000433138.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23157 AN: 151920 Hom.: 2025 Cov.: 32

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.172 AC: 43261 AN: 251230 Hom.: 4715 AF XY: 0.165 AC XY: 22434 AN XY: 135776

Gnomad AFR exome AF: 0.0967

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.00425

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.165 AC: 240476 AN: 1460908 Hom.: 21579 Cov.: 33 AF XY: 0.162 AC XY: 117585 AN XY: 726834

Gnomad4 AFR exome AF: 0.0951

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.152 AC: 23183 AN: 152038 Hom.: 2029 Cov.: 32 AF XY: 0.155 AC XY: 11521 AN XY: 74318

Gnomad4 AFR AF: 0.0982

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.00445

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.159

Alfa AF: 0.162 Hom.: 924

Bravo AF: 0.155

Asia WGS AF: 0.0760 AC: 263 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	-0.88
CADD	Benign	0.75
DANN	Benign	0.53

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: rs580253; hg19: chr11-104900488; COSMIC: COSV62056025; COSMIC: COSV62056025;