rs139133047

Variant names:

• chr4-3485583-A-G
• rs139133047
• NM_173660.5:c.577A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_173660.5(DOK7):​c.577A>G​(p.Ser193Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000332 in 1,607,594 control chromosomes in the GnomAD database, including 1 homozygotes. 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. S193N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 5.68
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3837803).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.577A>G	p.Ser193Gly	missense	Exon 5 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.577A>G	p.Ser193Gly	missense	Exon 5 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.145A>G	p.Ser49Gly	missense	Exon 3 of 8	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.577A>G	p.Ser193Gly	missense	Exon 5 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.235A>G		non_coding_transcript_exon	Exon 1 of 3
	DOK7	ENST00000643608.1		c.145A>G	p.Ser49Gly	missense	Exon 3 of 8	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152176 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000691

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000284 AC: 70 AN: 246148 AF XY: 0.000292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000329 AC: 479 AN: 1455300 Hom.: 1 Cov.: 33 AF XY: 0.000315 AC XY: 228 AN XY: 723856

African (AFR) AF: 0.0000904 AC: 3 AN: 33204

American (AMR) AF: 0.000316 AC: 14 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39176

South Asian (SAS) AF: 0.00 AC: 0 AN: 85398

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.000393 AC: 436 AN: 1108766

Other (OTH) AF: 0.000416 AC: 25 AN: 60106

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152294 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74460

African (AFR) AF: 0.0000962 AC: 4 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000567 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000276

EpiControl AF: 0.000840

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Congenital myasthenic syndrome 10 (1)
-	1	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.0040	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.20	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.046	D
PhyloP100		5.7
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.31	T
Vest4		0.55
MVP		0.92
ClinPred		0.44	T
GERP RS		3.4
Varity_R		0.81
Mutation Taster		=53/47	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: rs139133047; hg19: chr4-3487310;