rs61751523

Positions:

• chr11-105029174-T-C

Variant summary

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

The NM_001257118.3(CASP1):​c.956A>G​(p.Lys319Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,270 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (174 hom., cov: 32)
  • Exomes 𝑓: 0.014 (341 hom.)
• Consequence: CASP1 NM_001257118.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.651

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 (MetaRNN=0.002117306).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP1	NM_001257118.3	c.956A>G	p.Lys319Arg	missense_variant	7/9	ENST00000533400.6	NP_001244047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP1	ENST00000533400.6	c.956A>G	p.Lys319Arg	missense_variant	7/9	1	NM_001257118.3	ENSP00000433138.1

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5475 AN: 152128 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0891

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0438

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0420

GnomAD3 exomes AF: 0.0222 AC: 5576 AN: 250894 Hom.: 130 AF XY: 0.0213 AC XY: 2891 AN XY: 135590

Gnomad AFR exome AF: 0.0942

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.0463

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.00967

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0141 AC: 20612 AN: 1461024 Hom.: 341 Cov.: 31 AF XY: 0.0141 AC XY: 10235 AN XY: 726822

Gnomad4 AFR exome AF: 0.0966

Gnomad4 AMR exome AF: 0.0196

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.00895

Gnomad4 NFE exome AF: 0.00966

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0360 AC: 5477 AN: 152246 Hom.: 174 Cov.: 32 AF XY: 0.0353 AC XY: 2628 AN XY: 74458

Gnomad4 AFR AF: 0.0889

Gnomad4 AMR AF: 0.0253

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.0437

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0185 Hom.: 93

Bravo AF: 0.0402

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.0815 AC: 359

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0226 AC: 2743

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.0
DANN	Benign	0.61
DEOGEN2	Benign	0.010	T;.;.;T;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.043	T;T;T;.;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.98	.;.;.;L;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.65	N;N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.95	T;T;T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;B
Vest4		0.031, 0.028, 0.033, 0.034
MPC		0.13
ClinPred		0.0012	T
GERP RS		-0.82
Varity_R		0.23
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61751523; hg19: chr11-104899901;