4-3493358-GC-GCC

Position:

• chr4-3493358-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_173660.5(DOK7):​c.1378dupC​(p.Gln460fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,596,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: DOK7 NM_173660.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3493358-G-GC is Pathogenic according to our data. Variant chr4-3493358-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1378dupC	p.Gln460fs	frameshift_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1378dupC	p.Gln460fs	frameshift_variant	7/7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1	c.946dupC	p.Gln316fs	frameshift_variant	5/8			ENSP00000495701.1
DOK7	ENST00000515886.5	c.448dupC	p.Gln150fs	frameshift_variant	4/4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*599dupC		3_prime_UTR_variant	7/7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000527 AC: 11 AN: 208604 Hom.: 0 AF XY: 0.0000607 AC XY: 7 AN XY: 115332

Gnomad AFR exome AF: 0.0000858

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000354

Gnomad FIN exome AF: 0.000317

Gnomad NFE exome AF: 0.0000339

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 29 AN: 1444706 Hom.: 0 Cov.: 95 AF XY: 0.0000195 AC XY: 14 AN XY: 717054

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000235

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.000139

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152210 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74360

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	DOK7: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2024	PM2, PM3_strong, PS4_moderate, PVS1_strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2024	Frameshift variant predicted to result in protein elongation, as the last 45 amino acids are replaced with 58 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 32360404, Jadhav2019[casereport], 34418069, 33820833, 36308527, 28508085, 16917026, 18626973) -

Congenital myasthenic syndrome 10 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 27, 2022	- -

Fetal akinesia deformation sequence 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	Dec 12, 2022	- -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change results in a frameshift in the DOK7 gene (p.Gln460Profs*59). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the DOK7 protein and extend the protein by 13 additional amino acid residues. This variant is present in population databases (rs747302811, gnomAD 0.03%). This frameshift has been observed in individuals with congenital myasthenic syndrome (PMID: 16917026, 18626973). ClinVar contains an entry for this variant (Variation ID: 1282). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects DOK7 function (PMID: 18626973). This variant results in an extension of the DOK7 protein. Other variant(s) that result in a similarly extended protein product (p.Pro504Serfs*15) have been observed in individuals with DOK7-related disease (PMID: 16917026). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 05, 2024

ACMG categories: PVS1_mod,PS3,PS4,PM2_sup -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231133; hg19: chr4-3495085;