rs115733789

Variant names:

• chr1-62577354-T-C
• rs115733789
• NM_001367561.1:c.2020A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001367561.1(DOCK7):​c.2020A>G​(p.Met674Val) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,570,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.12
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18488169).

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.2020A>G	p.Met674Val	missense	Exon 18 of 50	NP_001354490.1
	DOCK7	NM_001330614.2		c.2020A>G	p.Met674Val	missense	Exon 18 of 50	NP_001317543.1
	DOCK7	NM_001271999.2		c.2020A>G	p.Met674Val	missense	Exon 18 of 49	NP_001258928.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.2020A>G	p.Met674Val	missense	Exon 18 of 50	ENSP00000489124.1
	DOCK7	ENST00000454575.6	TSL:1	c.2020A>G	p.Met674Val	missense	Exon 18 of 49	ENSP00000413583.2
	DOCK7	ENST00000912940.1		c.2020A>G	p.Met674Val	missense	Exon 18 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000748 AC: 18 AN: 240606 AF XY: 0.0000847

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000645

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000989

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 163 AN: 1418298 Hom.: 0 Cov.: 29 AF XY: 0.000127 AC XY: 89 AN XY: 702786

African (AFR) AF: 0.0000916 AC: 3 AN: 32754

American (AMR) AF: 0.000143 AC: 6 AN: 42100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25070

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39096

South Asian (SAS) AF: 0.000367 AC: 28 AN: 76350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.000110 AC: 120 AN: 1086920

Other (OTH) AF: 0.0000686 AC: 4 AN: 58324

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74502

African (AFR) AF: 0.000120 AC: 5 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

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: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		4.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.061	T
Sift4G	Benign	0.19	T
Polyphen		0.020	B
Vest4		0.59
MVP		0.61
MPC		0.39
ClinPred		0.039	T
GERP RS		5.2
Varity_R		0.43
gMVP		0.48
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs115733789; hg19: chr1-63043025;