4-109698378-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001226.4(CASP6):c.41-36A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,585,986 control chromosomes in the GnomAD database, including 323,135 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 0.68 (36403 hom., cov: 32)
  • Exomes 𝑓: 0.63 (286732 hom.)
• Consequence: CASP6 NM_001226.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP6	NM_001226.4	c.41-36A>C		intron_variant		ENST00000265164.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP6	ENST00000265164.7	c.41-36A>C		intron_variant		1	NM_001226.4	P1
CASP6	ENST00000352981.7	c.41-3678A>C		intron_variant		1
CASP6	ENST00000503684.5	c.-14-36A>C		intron_variant		3
CASP6	ENST00000505486.1	c.41-36A>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103809 AN: 151948 Hom.: 36325 Cov.: 32

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.646

GnomAD3 exomes AF: 0.648 AC: 157670 AN: 243496 Hom.: 51646 AF XY: 0.648 AC XY: 85440 AN XY: 131866

Gnomad AFR exome AF: 0.849

Gnomad AMR exome AF: 0.589

Gnomad ASJ exome AF: 0.584

Gnomad EAS exome AF: 0.596

Gnomad SAS exome AF: 0.744

Gnomad FIN exome AF: 0.667

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.623

GnomAD4 exome AF: 0.630 AC: 903819 AN: 1433920 Hom.: 286732 Cov.: 24 AF XY: 0.633 AC XY: 452150 AN XY: 714812

Gnomad4 AFR exome AF: 0.854

Gnomad4 AMR exome AF: 0.585

Gnomad4 ASJ exome AF: 0.576

Gnomad4 EAS exome AF: 0.557

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.666

Gnomad4 NFE exome AF: 0.619

Gnomad4 OTH exome AF: 0.637

GnomAD4 genome AF: 0.684 AC: 103949 AN: 152066 Hom.: 36403 Cov.: 32 AF XY: 0.683 AC XY: 50793 AN XY: 74352

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.578

Gnomad4 EAS AF: 0.581

Gnomad4 SAS AF: 0.738

Gnomad4 FIN AF: 0.666

Gnomad4 NFE AF: 0.621

Gnomad4 OTH AF: 0.651

Alfa AF: 0.644 Hom.: 9174

Bravo AF: 0.681

Asia WGS AF: 0.715 AC: 2484 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.0
Dann	Benign	0.62

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: rs2301717; hg19: chr4-110619534;