11-104998981-G-C

Variant names:

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

Variant summary

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

The NM_004347.5(CASP5):​c.1000C>G​(p.Leu334Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,611,652 control chromosomes in the GnomAD database, including 171,699 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 0.46 (16248 hom., cov: 31)
  • Exomes 𝑓: 0.46 (155451 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.049498E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

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>G	p.Leu334Val	missense	Exon 7 of 10	NP_004338.3	P51878-1
	CASP5	NM_001136112.3		c.1039C>G	p.Leu347Val	missense	Exon 7 of 10	NP_001129584.1	P51878-5
	CASP5	NM_001136109.3		c.826C>G	p.Leu276Val	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>G	p.Leu334Val	missense	Exon 7 of 10	ENSP00000260315.3	P51878-1
	CASP5	ENST00000393141.6	TSL:5	c.1039C>G	p.Leu347Val	missense	Exon 7 of 10	ENSP00000376849.2	P51878-5
	CASP5	ENST00000526056.5	TSL:5	c.1039C>G	p.Leu347Val	missense	Exon 7 of 9	ENSP00000436877.1	P51878-5

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69368 AN: 151850 Hom.: 16238 Cov.: 31

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.483

GnomAD2 exomes AF: 0.460 AC: 115379 AN: 250804 AF XY: 0.466

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.456 AC: 666026 AN: 1459686 Hom.: 155451 Cov.: 35 AF XY: 0.458 AC XY: 332617 AN XY: 726198

African (AFR) AF: 0.450 AC: 15050 AN: 33414

American (AMR) AF: 0.333 AC: 14858 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 13837 AN: 26072

East Asian (EAS) AF: 0.758 AC: 30049 AN: 39664

South Asian (SAS) AF: 0.480 AC: 41326 AN: 86036

European-Finnish (FIN) AF: 0.400 AC: 21346 AN: 53378

Middle Eastern (MID) AF: 0.588 AC: 3392 AN: 5764

European-Non Finnish (NFE) AF: 0.448 AC: 497161 AN: 1110416

Other (OTH) AF: 0.481 AC: 29007 AN: 60310

GnomAD4 genome AF: 0.457 AC: 69404 AN: 151966 Hom.: 16248 Cov.: 31 AF XY: 0.456 AC XY: 33883 AN XY: 74276

African (AFR) AF: 0.446 AC: 18470 AN: 41452

American (AMR) AF: 0.408 AC: 6229 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1867 AN: 3468

East Asian (EAS) AF: 0.762 AC: 3931 AN: 5160

South Asian (SAS) AF: 0.496 AC: 2395 AN: 4826

European-Finnish (FIN) AF: 0.410 AC: 4326 AN: 10548

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30581 AN: 67954

Other (OTH) AF: 0.482 AC: 1017 AN: 2108

Alfa AF: 0.457 Hom.: 11911

Bravo AF: 0.457

TwinsUK AF: 0.448 AC: 1663

ALSPAC AF: 0.463 AC: 1785

ESP6500AA AF: 0.443 AC: 1952

ESP6500EA AF: 0.459 AC: 3947

ExAC AF: 0.465 AC: 56417

Asia WGS AF: 0.613 AC: 2129 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.485

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.18
DANN	Benign	0.26
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00027	N
LIST_S2	Benign	0.056	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.80
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.018
Sift	Benign	0.53	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.20
ClinPred		0.00058	T
GERP RS		-4.7
Varity_R		0.030
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV52828754; COSMIC: COSV52828754;