11-105029761-G-A

Variant names:

• chr11-105029761-G-A
• rs580253
• NM_001257118.3:c.766C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 29 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257118.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP1	NM_001257118.3	MANE Select	c.766C>T	p.Leu256Leu	synonymous	Exon 6 of 9	NP_001244047.1
	CASP1	NM_033292.4		c.766C>T	p.Leu256Leu	synonymous	Exon 6 of 10	NP_150634.1
	CASP1	NM_001223.5		c.703C>T	p.Leu235Leu	synonymous	Exon 5 of 9	NP_001214.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP1	ENST00000533400.6	TSL:1 MANE Select	c.766C>T	p.Leu256Leu	synonymous	Exon 6 of 9	ENSP00000433138.1
	CASP1	ENST00000436863.7	TSL:1	c.766C>T	p.Leu256Leu	synonymous	Exon 6 of 10	ENSP00000410076.3
	CASP1	ENST00000526568.5	TSL:1	c.487C>T	p.Leu163Leu	synonymous	Exon 5 of 9	ENSP00000434250.1

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

GnomAD2 exomes AF: 0.172 AC: 43261 AN: 251230 AF XY: 0.165

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 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

African (AFR) AF: 0.0951 AC: 3181 AN: 33438

American (AMR) AF: 0.319 AC: 14264 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4408 AN: 26118

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39672

South Asian (SAS) AF: 0.108 AC: 9282 AN: 86250

European-Finnish (FIN) AF: 0.217 AC: 11569 AN: 53414

Middle Eastern (MID) AF: 0.115 AC: 662 AN: 5764

European-Non Finnish (NFE) AF: 0.169 AC: 187954 AN: 1111238

Other (OTH) AF: 0.150 AC: 9074 AN: 60348

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

African (AFR) AF: 0.0982 AC: 4074 AN: 41504

American (AMR) AF: 0.246 AC: 3753 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3470

East Asian (EAS) AF: 0.00445 AC: 23 AN: 5168

South Asian (SAS) AF: 0.111 AC: 535 AN: 4824

European-Finnish (FIN) AF: 0.217 AC: 2294 AN: 10578

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

European-Non Finnish (NFE) AF: 0.166 AC: 11300 AN: 67956

Other (OTH) AF: 0.159 AC: 335 AN: 2106

Alfa AF: 0.161 Hom.: 928

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.75
DANN	Benign	0.53
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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