NM_001257118.3:c.1036G>A

Variant names:

• chr11-105026922-C-T
• rs1863337232
• NM_001257118.3:c.1036G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM2 PP3_Strong BS2

The NM_001257118.3(CASP1):​c.1036G>A​(p.Gly346Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,452,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CASP1 NM_001257118.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP1	NM_001257118.3	MANE Select	c.1036G>A	p.Gly346Ser	missense	Exon 8 of 9	NP_001244047.1	P29466-1
	CASP1	NM_033292.4		c.1036G>A	p.Gly346Ser	missense	Exon 8 of 10	NP_150634.1	P29466-1
	CASP1	NM_001223.5		c.973G>A	p.Gly325Ser	missense	Exon 7 of 9	NP_001214.1	P29466-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP1	ENST00000533400.6	TSL:1 MANE Select	c.1036G>A	p.Gly346Ser	missense	Exon 8 of 9	ENSP00000433138.1	P29466-1
	CASP1	ENST00000436863.7	TSL:1	c.1036G>A	p.Gly346Ser	missense	Exon 8 of 10	ENSP00000410076.3	P29466-1
	CASP1	ENST00000526568.5	TSL:1	c.757G>A	p.Gly253Ser	missense	Exon 7 of 9	ENSP00000434250.1	P29466-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452020 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3 AN XY: 722942

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103264

Other (OTH) AF: 0.00 AC: 0 AN: 60070

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.98		Gain of disorder (P = 0.1074)
MVP		0.90
MPC		0.61
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.74
Mutation Taster		=49/51	disease causing

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: rs1863337232; hg19: chr11-104897649;