4-184632283-C-G

Variant names:

• chr4-184632283-C-G
• NM_004346.4:c.292G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004346.4(CASP3):​c.292G>C​(p.Glu98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP3 NM_004346.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.247
• Publications: 0 publications found

Genes affected

CASP3 (HGNC:1504): (caspase 3) The protein encoded by this gene is a cysteine-aspartic acid protease that plays a central role in the execution-phase of cell apoptosis. The encoded protein cleaves and inactivates poly(ADP-ribose) polymerase while it cleaves and activates sterol regulatory element binding proteins as well as caspases 6, 7, and 9. This protein itself is processed by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060240537).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004346.4. 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
	CASP3	NM_004346.4	MANE Select	c.292G>C	p.Glu98Gln	missense	Exon 5 of 8	NP_004337.2
	CASP3	NM_001354777.2		c.292G>C	p.Glu98Gln	missense	Exon 5 of 8	NP_001341706.1	P42574
	CASP3	NM_032991.3		c.292G>C	p.Glu98Gln	missense	Exon 4 of 7	NP_116786.1	P42574

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP3	ENST00000308394.9	TSL:1 MANE Select	c.292G>C	p.Glu98Gln	missense	Exon 5 of 8	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.292G>C	p.Glu98Gln	missense	Exon 4 of 7	ENSP00000428929.1	P42574
	CASP3	ENST00000393585.6	TSL:1	c.292G>C	p.Glu98Gln	missense	Exon 5 of 7	ENSP00000377210.2	A8MVM1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Benign	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.1
DANN	Benign	0.62
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.25
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.022
Sift	Benign	0.34	T
Sift4G	Benign	0.78	T
Polyphen		0.031	B
Vest4		0.080
MutPred		0.51		Loss of disorder (P = 0.0622)
MVP		0.53
MPC		0.61
ClinPred		0.070	T
GERP RS		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.23
gMVP		0.49
Mutation Taster		=90/10	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

hg19: chr4-185553437;