rs6831256

Variant names:

• chr4-3471412-A-G
• rs6831256
• NM_173660.5:c.101-1994A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173660.5(DOK7):​c.101-1994A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 152,064 control chromosomes in the GnomAD database, including 18,939 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18939 hom., cov: 34)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 76 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.612 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.101-1994A>G		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.101-1994A>G		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.100+7861A>G		intron	N/A	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.101-1994A>G		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.100+7861A>G		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.101-1994A>G		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74352 AN: 151946 Hom.: 18901 Cov.: 34

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.506

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.490 AC: 74452 AN: 152064 Hom.: 18939 Cov.: 34 AF XY: 0.491 AC XY: 36456 AN XY: 74314

African (AFR) AF: 0.619 AC: 25669 AN: 41494

American (AMR) AF: 0.543 AC: 8294 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1668 AN: 3462

East Asian (EAS) AF: 0.379 AC: 1946 AN: 5140

South Asian (SAS) AF: 0.510 AC: 2455 AN: 4818

European-Finnish (FIN) AF: 0.362 AC: 3833 AN: 10598

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29059 AN: 67948

Other (OTH) AF: 0.509 AC: 1075 AN: 2114

Alfa AF: 0.453 Hom.: 61971

Bravo AF: 0.505

Asia WGS AF: 0.453 AC: 1574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.42
PhyloP100		-1.5
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: rs6831256; hg19: chr4-3473139;