NM_173660.5:c.55-13C>G

Variant names:

• chr4-3463493-C-G
• rs886038744
• NM_173660.5:c.55-13C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_173660.5(DOK7):​c.55-13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,510,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.387
• 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: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-3463493-C-G is Benign according to our data. Variant chr4-3463493-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 262883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.55-13C>G		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.55-13C>G		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.55-13C>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.55-13C>G		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.55-13C>G		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.55-13C>G		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150182 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 5 AN: 1360132 Hom.: 0 Cov.: 54 AF XY: 0.00000596 AC XY: 4 AN XY: 670986

African (AFR) AF: 0.00 AC: 0 AN: 29138

American (AMR) AF: 0.0000287 AC: 1 AN: 34840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24292

East Asian (EAS) AF: 0.0000590 AC: 2 AN: 33894

South Asian (SAS) AF: 0.00 AC: 0 AN: 77108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3988

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1067156

Other (OTH) AF: 0.00 AC: 0 AN: 56608

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150182 Hom.: 0 Cov.: 25 AF XY: 0.0000136 AC XY: 1 AN XY: 73350

African (AFR) AF: 0.0000244 AC: 1 AN: 40914

American (AMR) AF: 0.00 AC: 0 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67166

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.56
PhyloP100		-0.39
PromoterAI		-0.13	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs886038744; hg19: chr4-3465220;