rs61751523

Variant names:

• chr11-105029174-T-C
• rs61751523
• NM_001257118.3:c.956A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033292.4(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. 15/21 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_033292.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.651
• Publications: 15 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 (MetaRNN=0.002117306).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0865 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033292.4. 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.956A>G	p.Lys319Arg	missense	Exon 7 of 9	NP_001244047.1
	CASP1	NM_033292.4		c.956A>G	p.Lys319Arg	missense	Exon 7 of 10	NP_150634.1
	CASP1	NM_001223.5		c.893A>G	p.Lys298Arg	missense	Exon 6 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.956A>G	p.Lys319Arg	missense	Exon 7 of 9	ENSP00000433138.1
	CASP1	ENST00000436863.7	TSL:1	c.956A>G	p.Lys319Arg	missense	Exon 7 of 10	ENSP00000410076.3
	CASP1	ENST00000526568.5	TSL:1	c.677A>G	p.Lys226Arg	missense	Exon 6 of 9	ENSP00000434250.1

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

GnomAD2 exomes AF: 0.0222 AC: 5576 AN: 250894 AF XY: 0.0213

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 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

African (AFR) AF: 0.0966 AC: 3227 AN: 33414

American (AMR) AF: 0.0196 AC: 874 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 752 AN: 26104

East Asian (EAS) AF: 0.0290 AC: 1152 AN: 39668

South Asian (SAS) AF: 0.0219 AC: 1890 AN: 86230

European-Finnish (FIN) AF: 0.00895 AC: 478 AN: 53398

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5760

European-Non Finnish (NFE) AF: 0.00966 AC: 10735 AN: 1111486

Other (OTH) AF: 0.0207 AC: 1248 AN: 60344

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

African (AFR) AF: 0.0889 AC: 3694 AN: 41538

American (AMR) AF: 0.0253 AC: 386 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3468

East Asian (EAS) AF: 0.0437 AC: 226 AN: 5174

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4820

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10626

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 766 AN: 68018

Other (OTH) AF: 0.0416 AC: 88 AN: 2116

Alfa AF: 0.0198 Hom.: 243

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 v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.043	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.65
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.018
Sift	Benign	0.95	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.13
ClinPred		0.0012	T
GERP RS		-0.82
Varity_R		0.23
gMVP		0.17
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61751523; hg19: chr11-104899901; COSMIC: COSV107435466; COSMIC: COSV107435466;