rs748239649

Variant names:

• chr11-104995826-T-C
• rs748239649
• NM_004347.5:c.1223A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-104995826-T-C
• chr11-104995826-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004347.5(CASP5):​c.1223A>G​(p.Glu408Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,458,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

Genes affected

CASP5 (HGNC:1506): (caspase 5) This gene encodes 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 two subunits, large and small, that dimerize to form the active enzyme. Overexpression of the active form of this enzyme induces apoptosis in fibroblasts. Max, a central component of the Myc/Max/Mad transcription regulation network important for cell growth, differentiation, and apoptosis, is cleaved by this protein; this process requires Fas-mediated dephosphorylation of Max. The expression of this gene is regulated by interferon-gamma and lipopolysaccharide. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

ENSG00000303891 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004347.5. 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
	CASP5	NM_004347.5	MANE Select	c.1223A>G	p.Glu408Gly	missense	Exon 9 of 10	NP_004338.3	P51878-1
	CASP5	NM_001136112.3		c.1262A>G	p.Glu421Gly	missense	Exon 9 of 10	NP_001129584.1	P51878-5
	CASP5	NM_001136109.3		c.1049A>G	p.Glu350Gly	missense	Exon 8 of 9	NP_001129581.1	P51878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP5	ENST00000260315.8	TSL:5 MANE Select	c.1223A>G	p.Glu408Gly	missense	Exon 9 of 10	ENSP00000260315.3	P51878-1
	CASP5	ENST00000393141.6	TSL:5	c.1262A>G	p.Glu421Gly	missense	Exon 9 of 10	ENSP00000376849.2	P51878-5
	CASP5	ENST00000526056.5	TSL:5	c.1262A>G	p.Glu421Gly	missense	Exon 9 of 9	ENSP00000436877.1	P51878-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250134 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1458558 Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 6 AN XY: 725718

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1109410

Other (OTH) AF: 0.00 AC: 0 AN: 60262

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

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	Uncertain	0.44
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.093
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.6
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.64		Gain of catalytic residue at V409 (P = 0.0402)
MVP		0.51
MPC		0.84
ClinPred		0.98	D
GERP RS		1.6
Varity_R		0.78
gMVP		0.50
Mutation Taster		=94/6	polymorphism

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: rs748239649; hg19: chr11-104866553;