rs2696057

Variant names:

• chr4-184634680-C-G
• rs2696057
• NM_004346.4:c.178+614G>C

Variant summary

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

The NM_004346.4(CASP3):​c.178+614G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 152,210 control chromosomes in the GnomAD database, including 59,722 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (59722 hom., cov: 31)
• Consequence: CASP3 NM_004346.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.202
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

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.178+614G>C		intron	N/A	NP_004337.2
	CASP3	NM_001354777.2		c.178+614G>C		intron	N/A	NP_001341706.1	P42574
	CASP3	NM_032991.3		c.178+614G>C		intron	N/A	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.178+614G>C		intron	N/A	ENSP00000311032.4	P42574
	CASP3	ENST00000523916.5	TSL:1	c.178+614G>C		intron	N/A	ENSP00000428929.1	P42574
	CASP3	ENST00000393585.6	TSL:1	c.178+614G>C		intron	N/A	ENSP00000377210.2	A8MVM1

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134458 AN: 152092 Hom.: 59652 Cov.: 31

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.830

Gnomad ASJ AF: 0.848

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.868

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.884 AC: 134590 AN: 152210 Hom.: 59722 Cov.: 31 AF XY: 0.886 AC XY: 65932 AN XY: 74410

African (AFR) AF: 0.953 AC: 39586 AN: 41540

American (AMR) AF: 0.830 AC: 12688 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 2943 AN: 3470

East Asian (EAS) AF: 0.882 AC: 4550 AN: 5158

South Asian (SAS) AF: 0.874 AC: 4214 AN: 4820

European-Finnish (FIN) AF: 0.923 AC: 9788 AN: 10606

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.852 AC: 57960 AN: 68006

Other (OTH) AF: 0.871 AC: 1840 AN: 2112

Alfa AF: 0.872 Hom.: 7259

Bravo AF: 0.879

Asia WGS AF: 0.878 AC: 3055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.50
DANN	Benign	0.39
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs2696057; hg19: chr4-185555834;