13-98800361-C-T

Variant names:

• chr13-98800361-C-T
• rs201927938
• NM_001366683.2:c.5843G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001366683.2(DOCK9):​c.5843G>A​(p.Arg1948Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DOCK9 NM_001366683.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06
• Publications: 4 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024852484).
• BS2: High AC in GnomAd4 at 70 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366683.2. 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
	DOCK9	NM_001366683.2	MANE Select	c.5843G>A	p.Arg1948Gln	missense	Exon 50 of 53	NP_001353612.1	A0A804HIE8
	DOCK9	NM_001366681.2		c.5948G>A	p.Arg1983Gln	missense	Exon 52 of 55	NP_001353610.1
	DOCK9	NM_001366684.2		c.5912G>A	p.Arg1971Gln	missense	Exon 51 of 54	NP_001353613.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK9	ENST00000682017.1	MANE Select	c.5843G>A	p.Arg1948Gln	missense	Exon 50 of 53	ENSP00000507034.1	A0A804HIE8
	DOCK9	ENST00000903387.1		c.5843G>A	p.Arg1948Gln	missense	Exon 51 of 54	ENSP00000573446.1
	DOCK9	ENST00000448493.7	TSL:5	c.5810G>A	p.Arg1937Gln	missense	Exon 50 of 53	ENSP00000401958.4	A0A088AWN3

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000351 AC: 87 AN: 248180 AF XY: 0.000356

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000297 AC: 434 AN: 1461302 Hom.: 0 Cov.: 30 AF XY: 0.000289 AC XY: 210 AN XY: 726850

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00103 AC: 46 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000332 AC: 369 AN: 1111728

Other (OTH) AF: 0.000298 AC: 18 AN: 60352

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74410

African (AFR) AF: 0.000120 AC: 5 AN: 41518

American (AMR) AF: 0.00288 AC: 44 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000419

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000382

EpiControl AF: 0.000357

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	-0.18
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.069
Sift	Benign	0.62	T
Sift4G	Benign	0.69	T
Polyphen		0.33	B
Vest4		0.16
MVP		0.78
MPC		0.60
ClinPred		0.029	T
GERP RS		5.3
gMVP		0.53
Mutation Taster		=72/28	polymorphism

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: rs201927938; hg19: chr13-99452615; COSMIC: COSV59621470;