NM_001367561.1:c.2471T>C

Variant names:

• chr1-62555950-A-G
• rs35400360
• NM_001367561.1:c.2471T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367561.1(DOCK7):​c.2471T>C​(p.Ile824Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,854 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I824S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.32
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068542957).
• BP6: Variant 1-62555950-A-G is Benign according to our data. Variant chr1-62555950-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1745/152328) while in subpopulation AFR AF = 0.0396 (1648/41574). AF 95% confidence interval is 0.038. There are 44 homozygotes in GnomAd4. There are 835 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

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.2471T>C	p.Ile824Thr	missense	Exon 21 of 50	NP_001354490.1	Q96N67-1
	DOCK7	NM_001330614.2		c.2471T>C	p.Ile824Thr	missense	Exon 21 of 50	NP_001317543.1	Q96N67-6
	DOCK7	NM_001271999.2		c.2471T>C	p.Ile824Thr	missense	Exon 21 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.2471T>C	p.Ile824Thr	missense	Exon 21 of 50	ENSP00000489124.1	Q96N67-1
	DOCK7	ENST00000454575.6	TSL:1	c.2471T>C	p.Ile824Thr	missense	Exon 21 of 49	ENSP00000413583.2	Q96N67-2
	DOCK7	ENST00000912940.1		c.2471T>C	p.Ile824Thr	missense	Exon 21 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1744 AN: 152210 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

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: 0.000265

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00302 AC: 758 AN: 251164 AF XY: 0.00223

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00122 AC: 1789 AN: 1461526 Hom.: 30 Cov.: 31 AF XY: 0.00105 AC XY: 767 AN XY: 727054

African (AFR) AF: 0.0425 AC: 1422 AN: 33472

American (AMR) AF: 0.00259 AC: 116 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111892

Other (OTH) AF: 0.00270 AC: 163 AN: 60378

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 152328 Hom.: 44 Cov.: 32 AF XY: 0.0112 AC XY: 835 AN XY: 74484

African (AFR) AF: 0.0396 AC: 1648 AN: 41574

American (AMR) AF: 0.00392 AC: 60 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68030

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00475 Hom.: 21

Bravo AF: 0.0130

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00365 AC: 443

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.25
Sift	Benign	0.042	D
Sift4G	Uncertain	0.032	D
Polyphen		0.15	B
Vest4		0.93
MVP		0.27
MPC		0.61
ClinPred		0.045	T
GERP RS		5.5
Varity_R		0.35
gMVP		0.67
Mutation Taster		=93/7	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: rs35400360; hg19: chr1-63021621;