chr4-109698378-T-G

Variant names:

• chr4-109698378-T-G
• rs2301717
• NM_001226.4:c.41-36A>C

Variant summary

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

The NM_001226.4(CASP6):​c.41-36A>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
• Publications: 18 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=-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 rank	MANE	Protein	UniProt
CASP6	NM_001226.4	c.41-36A>C		intron_variant	Intron 1 of 6	ENST00000265164.7	NP_001217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP6	ENST00000265164.7	c.41-36A>C		intron_variant	Intron 1 of 6	1	NM_001226.4	ENSP00000265164.2
CASP6	ENST00000352981.7	c.41-3678A>C		intron_variant	Intron 1 of 3	1		ENSP00000285333.3
CASP6	ENST00000503684.5	c.-14-36A>C		intron_variant	Intron 1 of 4	3		ENSP00000427669.1
CASP6	ENST00000505486.2	n.41-36A>C		intron_variant	Intron 1 of 5			ENSP00000424080.1

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

GnomAD2 exomes AF: 0.648 AC: 157670 AN: 243496 AF XY: 0.648

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 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

African (AFR) AF: 0.854 AC: 27865 AN: 32616

American (AMR) AF: 0.585 AC: 25199 AN: 43056

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 14820 AN: 25740

East Asian (EAS) AF: 0.557 AC: 21951 AN: 39418

South Asian (SAS) AF: 0.738 AC: 62275 AN: 84396

European-Finnish (FIN) AF: 0.666 AC: 35011 AN: 52586

Middle Eastern (MID) AF: 0.654 AC: 3674 AN: 5622

European-Non Finnish (NFE) AF: 0.619 AC: 675212 AN: 1091114

Other (OTH) AF: 0.637 AC: 37812 AN: 59372

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

African (AFR) AF: 0.846 AC: 35081 AN: 41470

American (AMR) AF: 0.582 AC: 8899 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2002 AN: 3462

East Asian (EAS) AF: 0.581 AC: 3011 AN: 5180

South Asian (SAS) AF: 0.738 AC: 3558 AN: 4820

European-Finnish (FIN) AF: 0.666 AC: 7037 AN: 10566

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42190 AN: 67976

Other (OTH) AF: 0.651 AC: 1374 AN: 2112

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
PhyloP100		-0.27
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: rs2301717; hg19: chr4-110619534;