1-62457538-C-T

Variant names:

• chr1-62457538-C-T
• rs779747783
• NM_001367561.1:c.6380G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001367561.1(DOCK7):​c.6380G>A​(p.Arg2127Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R2127R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46
• Publications: 0 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.6380G>A	p.Arg2127Lys	missense splice_region	Exon 49 of 50	NP_001354490.1	Q96N67-1
	DOCK7	NM_001330614.2		c.6353G>A	p.Arg2118Lys	missense splice_region	Exon 49 of 50	NP_001317543.1	Q96N67-6
	DOCK7	NM_001271999.2		c.6347G>A	p.Arg2116Lys	missense splice_region	Exon 48 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.6380G>A	p.Arg2127Lys	missense splice_region	Exon 49 of 50	ENSP00000489124.1	Q96N67-1
	DOCK7	ENST00000454575.6	TSL:1	c.6347G>A	p.Arg2116Lys	missense splice_region	Exon 48 of 49	ENSP00000413583.2	Q96N67-2
	DOCK7	ENST00000912940.1		c.6374G>A	p.Arg2125Lys	missense splice_region	Exon 48 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249754 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460336 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726446

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111496

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.24
Sift	Uncertain	0.022	D
Sift4G	Benign	0.065	T
Polyphen		0.34	B
Vest4		0.59
MutPred		0.38		Gain of methylation at R2116 (P = 0.0316)
MVP		0.61
MPC		0.50
ClinPred		0.86	D
GERP RS		6.0
Varity_R		0.51
gMVP		0.69
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.15		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: rs779747783; hg19: chr1-62923209;