11-104998981-G-C

Position:

• chr11-104998981-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP5	NM_004347.5	c.1000C>G	p.Leu334Val	missense_variant	7/10	ENST00000260315.8	NP_004338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP5	ENST00000260315.8	c.1000C>G	p.Leu334Val	missense_variant	7/10	5	NM_004347.5	ENSP00000260315	A2

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

GnomAD3 exomes AF: 0.460 AC: 115379 AN: 250804 Hom.: 27951 AF XY: 0.466 AC XY: 63212 AN XY: 135532

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 SAS exome AF: 0.476

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

Gnomad4 AFR exome AF: 0.450

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.531

Gnomad4 EAS exome AF: 0.758

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.400

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.481

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

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.762

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.482

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 v4.3

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;T;T;T;.;.
MetaRNN	Benign	0.0000020	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	.;.;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.74	N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.53	T;T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.0070
MPC		0.20
ClinPred		0.00058	T
GERP RS		-4.7
Varity_R		0.030
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs523104; hg19: chr11-104869708; COSMIC: COSV52828754; COSMIC: COSV52828754;