rs2006802

Variant names:

• chr4-3485708-G-A
• rs2006802
• NM_173660.5:c.652+50G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.652+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,475,030 control chromosomes in the GnomAD database, including 1,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (969 hom., cov: 34)
  • Exomes 𝑓: 0.0084 (804 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.589
• Publications: 3 publications found

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-3485708-G-A is Benign according to our data. Variant chr4-3485708-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.652+50G>A		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.652+50G>A		intron	N/A	NP_001288000.1
	DOK7	NM_001363811.2		c.220+50G>A		intron	N/A	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.652+50G>A		intron	N/A	ENSP00000344432.5
	DOK7	ENST00000513995.1	TSL:1	n.310+50G>A		intron	N/A
	DOK7	ENST00000643608.1		c.220+50G>A		intron	N/A	ENSP00000495701.1

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9812 AN: 152182 Hom.: 965 Cov.: 34

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0171 AC: 2261 AN: 132148 AF XY: 0.0137

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00469

Gnomad FIN exome AF: 0.0000674

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.00838 AC: 11080 AN: 1322730 Hom.: 804 Cov.: 33 AF XY: 0.00774 AC XY: 5012 AN XY: 647248

African (AFR) AF: 0.218 AC: 6198 AN: 28418

American (AMR) AF: 0.0171 AC: 506 AN: 29536

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 235 AN: 21662

East Asian (EAS) AF: 0.00273 AC: 89 AN: 32640

South Asian (SAS) AF: 0.00513 AC: 344 AN: 67116

European-Finnish (FIN) AF: 0.000108 AC: 5 AN: 46370

Middle Eastern (MID) AF: 0.0200 AC: 102 AN: 5108

European-Non Finnish (NFE) AF: 0.00251 AC: 2609 AN: 1037726

Other (OTH) AF: 0.0183 AC: 992 AN: 54154

GnomAD4 genome AF: 0.0646 AC: 9835 AN: 152300 Hom.: 969 Cov.: 34 AF XY: 0.0624 AC XY: 4650 AN XY: 74474

African (AFR) AF: 0.215 AC: 8913 AN: 41548

American (AMR) AF: 0.0314 AC: 480 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00340 AC: 231 AN: 68024

Other (OTH) AF: 0.0549 AC: 116 AN: 2112

Alfa AF: 0.0298 Hom.: 65

Bravo AF: 0.0724

Asia WGS AF: 0.0230 AC: 82 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.60
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs2006802; hg19: chr4-3487435;