rs1553850100

Variant names:

• chr4-3493006-C-CGCCACTGGCAGCCACTCCT
• rs1553850100
• NM_173660.5:c.1021_1039dupGCCACTGGCAGCCACTCCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_173660.5(DOK7):​c.1021_1039dupGCCACTGGCAGCCACTCCT​(p.Ser347CysfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,594 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DOK7 NM_173660.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.87
• 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: 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: Pathogenic. The variant received 10 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 54 pathogenic variants in the truncated region.
• PP5: Variant 4-3493006-C-CGCCACTGGCAGCCACTCCT is Pathogenic according to our data. Variant chr4-3493006-C-CGCCACTGGCAGCCACTCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 434960.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1021_1039dupGCCACTGGCAGCCACTCCT	p.Ser347CysfsTer28	frameshift_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1021_1039dupGCCACTGGCAGCCACTCCT	p.Ser347CysfsTer28	frameshift_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410594 Hom.: 0 Cov.: 111 AF XY: 0.00 AC XY: 0 AN XY: 698602

African (AFR) AF: 0.00 AC: 0 AN: 32690

American (AMR) AF: 0.00 AC: 0 AN: 38316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.00 AC: 0 AN: 37426

South Asian (SAS) AF: 0.00 AC: 0 AN: 81528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090934

Other (OTH) AF: 0.00 AC: 0 AN: 58692

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 10 Pathogenic:1

Nov 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553850100; hg19: chr4-3494733;