NM_001367561.1:c.2605G>A

Variant names:

• chr1-62552893-C-T
• rs201823761
• NM_001367561.1:c.2605G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001367561.1(DOCK7):​c.2605G>A​(p.Gly869Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000734 in 1,604,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G869A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 5.74
• Publications: 4 publications found

Genes affected

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

DOCK7 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 23

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011288434).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367561.1. 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
	DOCK7	NM_001367561.1	MANE Select	c.2605G>A	p.Gly869Ser	missense	Exon 22 of 50	NP_001354490.1	Q96N67-1
	DOCK7	NM_001330614.2		c.2605G>A	p.Gly869Ser	missense	Exon 22 of 50	NP_001317543.1	Q96N67-6
	DOCK7	NM_001271999.2		c.2605G>A	p.Gly869Ser	missense	Exon 22 of 49	NP_001258928.1	Q96N67-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.2605G>A	p.Gly869Ser	missense	Exon 22 of 50	ENSP00000489124.1	Q96N67-1
	DOCK7	ENST00000454575.6	TSL:1	c.2605G>A	p.Gly869Ser	missense	Exon 22 of 49	ENSP00000413583.2	Q96N67-2
	DOCK7	ENST00000912940.1		c.2605G>A	p.Gly869Ser	missense	Exon 22 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes AF: 0.000659 AC: 100 AN: 151840 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00338

GnomAD2 exomes AF: 0.000589 AC: 145 AN: 246258 AF XY: 0.000608

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.000742 AC: 1077 AN: 1452254 Hom.: 0 Cov.: 30 AF XY: 0.000716 AC XY: 517 AN XY: 722256

African (AFR) AF: 0.000151 AC: 5 AN: 33206

American (AMR) AF: 0.00161 AC: 71 AN: 44096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 84210

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53022

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5736

European-Non Finnish (NFE) AF: 0.000857 AC: 948 AN: 1106828

Other (OTH) AF: 0.000817 AC: 49 AN: 59948

GnomAD4 genome AF: 0.000658 AC: 100 AN: 151958 Hom.: 0 Cov.: 31 AF XY: 0.000592 AC XY: 44 AN XY: 74272

African (AFR) AF: 0.000290 AC: 12 AN: 41410

American (AMR) AF: 0.000721 AC: 11 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 67994

Other (OTH) AF: 0.00334 AC: 7 AN: 2096

Alfa AF: 0.000700 Hom.: 0

Bravo AF: 0.000797

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000478 AC: 58

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Developmental and epileptic encephalopathy, 23 (4)
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N
PhyloP100		5.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.16
Sift	Benign	0.40	T
Sift4G	Benign	0.69	T
Polyphen		0.0080	B
Vest4		0.53
MVP		0.59
MPC		0.38
ClinPred		0.030	T
GERP RS		5.0
PromoterAI		-0.0042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.61
Mutation Taster		=60/40	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: rs201823761; hg19: chr1-63018564;