rs2274643

Variant names:

• chr13-98888246-A-G
• rs2274643
• NM_001366683.2:c.1978-23T>C

Variant summary

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

The NM_001366683.2(DOCK9):​c.1978-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,605,090 control chromosomes in the GnomAD database, including 269,571 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 0.53 (21769 hom., cov: 32)
  • Exomes 𝑓: 0.58 (247802 hom.)
• Consequence: DOCK9 NM_001366683.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241
• Publications: 8 publications found

Genes affected

DOCK9 (HGNC:14132): (dedicator of cytokinesis 9) Enables cadherin binding activity. Predicted to be involved in positive regulation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DOCK9 Gene-Disease associations (from GenCC):

• keratoconus

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK9	NM_001366683.2	c.1978-23T>C		intron_variant	Intron 17 of 52	ENST00000682017.1	NP_001353612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK9	ENST00000682017.1	c.1978-23T>C		intron_variant	Intron 17 of 52		NM_001366683.2	ENSP00000507034.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80285 AN: 151924 Hom.: 21768 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.561

GnomAD2 exomes AF: 0.543 AC: 129674 AN: 238768 AF XY: 0.550

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.586

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.581 AC: 843578 AN: 1453048 Hom.: 247802 Cov.: 33 AF XY: 0.580 AC XY: 418720 AN XY: 722382

African (AFR) AF: 0.424 AC: 13966 AN: 32904

American (AMR) AF: 0.531 AC: 22823 AN: 43002

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15061 AN: 25886

East Asian (EAS) AF: 0.341 AC: 13503 AN: 39608

South Asian (SAS) AF: 0.560 AC: 47123 AN: 84134

European-Finnish (FIN) AF: 0.558 AC: 29705 AN: 53192

Middle Eastern (MID) AF: 0.595 AC: 3417 AN: 5740

European-Non Finnish (NFE) AF: 0.599 AC: 663773 AN: 1108498

Other (OTH) AF: 0.569 AC: 34207 AN: 60084

GnomAD4 genome AF: 0.528 AC: 80309 AN: 152042 Hom.: 21769 Cov.: 32 AF XY: 0.525 AC XY: 39043 AN XY: 74310

African (AFR) AF: 0.432 AC: 17918 AN: 41456

American (AMR) AF: 0.562 AC: 8596 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1995 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1703 AN: 5174

South Asian (SAS) AF: 0.540 AC: 2606 AN: 4822

European-Finnish (FIN) AF: 0.556 AC: 5867 AN: 10546

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39674 AN: 67974

Other (OTH) AF: 0.564 AC: 1189 AN: 2110

Alfa AF: 0.548 Hom.: 8094

Bravo AF: 0.528

Asia WGS AF: 0.449 AC: 1560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.48
PhyloP100		-0.24
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: rs2274643; hg19: chr13-99540500; COSMIC: COSV59647363;