chr4-109699300-T-C

Variant names:

• chr4-109699300-T-C
• rs768063
• NM_001226.4:c.41-958A>G

Variant summary

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

The NM_001226.4(CASP6):​c.41-958A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 152,278 control chromosomes in the GnomAD database, including 72,482 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 0.98 (72482 hom., cov: 31)
• Consequence: CASP6 NM_001226.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 7 publications found

Genes affected

CASP6 (HGNC:1507): (caspase 6) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family of enzymes. 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 acid residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Alternative splicing of this gene results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001226.4. 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
	CASP6	NM_001226.4	MANE Select	c.41-958A>G		intron	N/A	NP_001217.2
	CASP6	NM_032992.3		c.40+4056A>G		intron	N/A	NP_116787.1	P55212-2
	CASP6	NR_133012.2		n.91-958A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP6	ENST00000265164.7	TSL:1 MANE Select	c.41-958A>G		intron	N/A	ENSP00000265164.2	P55212-1
	CASP6	ENST00000352981.7	TSL:1	c.40+4056A>G		intron	N/A	ENSP00000285333.3	P55212-2
	CASP6	ENST00000503684.5	TSL:3	c.-14-958A>G		intron	N/A	ENSP00000427669.1	D6RHU3

Frequencies

GnomAD3 genomes AF: 0.976 AC: 148434 AN: 152160 Hom.: 72421 Cov.: 31

Gnomad AFR AF: 0.994

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.965

Gnomad OTH AF: 0.976

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

GnomAD4 genome AF: 0.976 AC: 148554 AN: 152278 Hom.: 72482 Cov.: 31 AF XY: 0.976 AC XY: 72646 AN XY: 74460

African (AFR) AF: 0.994 AC: 41293 AN: 41552

American (AMR) AF: 0.978 AC: 14972 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3186 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5171 AN: 5172

South Asian (SAS) AF: 0.944 AC: 4556 AN: 4824

European-Finnish (FIN) AF: 0.986 AC: 10455 AN: 10606

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.965 AC: 65675 AN: 68034

Other (OTH) AF: 0.976 AC: 2057 AN: 2108

Alfa AF: 0.965 Hom.: 66440

Bravo AF: 0.977

Asia WGS AF: 0.981 AC: 3412 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.015
DANN	Benign	0.42
PhyloP100		-1.3
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: rs768063; hg19: chr4-110620456;