11-104998981-G-T

Variant names:

• chr11-104998981-G-T
• rs523104
• NM_004347.5:c.1000C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004347.5(CASP5):​c.1000C>A​(p.Leu334Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CASP5 NM_004347.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801
• Publications: 47 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073545784).

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.1000C>A	p.Leu334Ile	missense	Exon 7 of 10	NP_004338.3	P51878-1
	CASP5	NM_001136112.3		c.1039C>A	p.Leu347Ile	missense	Exon 7 of 10	NP_001129584.1	P51878-5
	CASP5	NM_001136109.3		c.826C>A	p.Leu276Ile	missense	Exon 6 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.1000C>A	p.Leu334Ile	missense	Exon 7 of 10	ENSP00000260315.3	P51878-1
	CASP5	ENST00000393141.6	TSL:5	c.1039C>A	p.Leu347Ile	missense	Exon 7 of 10	ENSP00000376849.2	P51878-5
	CASP5	ENST00000526056.5	TSL:5	c.1039C>A	p.Leu347Ile	missense	Exon 7 of 9	ENSP00000436877.1	P51878-5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151922 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250804 AF XY: 0.00000738

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461360 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111634

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151922 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74196

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 11911

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.78
DANN	Benign	0.53
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.80
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.014
Sift	Benign	0.40	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.093
MutPred		0.36		Gain of catalytic residue at S336 (P = 0.0339)
MVP		0.18
MPC		0.21
ClinPred		0.025	T
GERP RS		-4.7
Varity_R		0.042
gMVP		0.11
Mutation Taster		=98/2	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: rs523104; hg19: chr11-104869708;