chr4-3493106-A-AGCCT

Variant names:

• chr4-3493106-A-AGCCT
• rs606231128
• NM_173660.5:c.1124_1127dupTGCC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_173660.5(DOK7):​c.1124_1127dupTGCC​(p.Ala378SerfsTer30) variant causes a frameshift change. The variant allele was found at a frequency of 0.00111 in 1,584,152 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002768618: In addition, functional studies showed that this variant causes impaired protein function, affecting the neuromuscular junction (Beeson, D. et al. (2006))." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P376P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DOK7 NM_173660.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:33 O:2
• Conservation: PhyloP100: 6.82
• Publications: 52 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: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 51 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002768618: In addition, functional studies showed that this variant causes impaired protein function, affecting the neuromuscular junction (Beeson, D. et al. (2006)).; SCV004048461: Experimental studies have shown that this variant affects the phosphorylation of MuSK and also affects the ability of DOK7 protein to produce properly formed AChR clusters (Beeson D. et. al., 2006; Skalak R. et. al., 1990).; SCV000567740: Published functional studies demonstrate that this variant impairs activity and its ability to induce AChR clustering (Beeson et al., 2006; Cossins et al., 2012); PMID: 26501342, 29395672, 29315608, 18626973, 32403337, 18161030, 30487145, 22661499, 26583494, 29054425, 29118959, 23657916, 33726816, 31453852, 32238315, 31447096, 30609409, 31127727, 31980526, 34103343, 34426522, 32528171, 33146414, 16917026; SCV000711740: "In vitro functional studies suggest that this truncation impacts protein function (Beeson 2006 PMID: 16917026)."; SCV004223317: One publication reports in vitro experimental evidence evaluating an impact on protein function, however, additional evidence is needed to provide convincing conclusions about the variant effect in vivo (e.g. Hamuro_2008).; SCV000640935: Experimental studies have shown that this premature translational stop signal affects DOK7 function (PMID: 2261499, 16917026, 18165682, 18626973, 25237101).
• PP5: Variant 4-3493106-A-AGCCT is Pathogenic according to our data. Variant chr4-3493106-A-AGCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 1273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1124_1127dupTGCC	p.Ala378SerfsTer30	frameshift	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1124_1127dupTGCC	p.Ala378SerfsTer30	frameshift	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.692_695dupTGCC	p.Ala234SerfsTer30	frameshift	Exon 5 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.1124_1127dupTGCC	p.Ala378SerfsTer30	frameshift	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.692_695dupTGCC	p.Ala234SerfsTer30	frameshift	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000515886.5	TSL:2	c.194_197dupTGCC	p.Ala68SerfsTer30	frameshift	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152186 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000635 AC: 123 AN: 193594 AF XY: 0.000591

Gnomad AFR exome AF: 0.0000913

Gnomad AMR exome AF: 0.000771

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000735

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000398

GnomAD4 exome AF: 0.00114 AC: 1637 AN: 1431848 Hom.: 2 Cov.: 112 AF XY: 0.00112 AC XY: 794 AN XY: 710568

African (AFR) AF: 0.000152 AC: 5 AN: 33002

American (AMR) AF: 0.000755 AC: 31 AN: 41052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 37920

South Asian (SAS) AF: 0.000819 AC: 68 AN: 83060

European-Finnish (FIN) AF: 0.0000888 AC: 4 AN: 45042

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00133 AC: 1469 AN: 1101030

Other (OTH) AF: 0.000994 AC: 59 AN: 59348

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152304 Hom.: 0 Cov.: 34 AF XY: 0.000712 AC XY: 53 AN XY: 74484

African (AFR) AF: 0.000241 AC: 10 AN: 41576

American (AMR) AF: 0.000784 AC: 12 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.000676

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Congenital myasthenic syndrome 10 (10)
10	-	-	not provided (10)
4	-	-	Fetal akinesia deformation sequence 3 (4)
2	-	-	Congenital myasthenic syndrome (3)
2	-	-	Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 (3)
1	-	-	DOK7-related disorder (1)
1	-	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Ritscher-Schinzel syndrome 2 (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs606231128; hg19: chr4-3494833;