4-3493384-GCCTGGC-GCCTGGCCCTGGC

Position:

• chr4-3493384-GCCTGGC-GCCTGGCCCTGGC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_173660.5(DOK7):​c.1403_1408dupGCCCTG​(p.Gly468_Pro469dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,594,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: DOK7 NM_173660.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.660

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_173660.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1403_1408dupGCCCTG	p.Gly468_Pro469dup	disruptive_inframe_insertion	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1403_1408dupGCCCTG	p.Gly468_Pro469dup	disruptive_inframe_insertion	7/7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1	c.971_976dupGCCCTG	p.Gly324_Pro325dup	disruptive_inframe_insertion	5/8			ENSP00000495701.1
DOK7	ENST00000515886.5	c.473_478dupGCCCTG	p.Gly158_Pro159dup	disruptive_inframe_insertion	4/4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*624_*629dupGCCCTG		3_prime_UTR_variant	7/7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152240 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000295 AC: 59 AN: 200306 Hom.: 0 AF XY: 0.000307 AC XY: 34 AN XY: 110612

Gnomad AFR exome AF: 0.0000913

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.000573 AC: 826 AN: 1442016 Hom.: 0 Cov.: 89 AF XY: 0.000555 AC XY: 397 AN XY: 715754

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.0000399

Gnomad4 NFE exome AF: 0.000711

Gnomad4 OTH exome AF: 0.000453

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152240 Hom.: 0 Cov.: 35 AF XY: 0.000134 AC XY: 10 AN XY: 74380

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000283

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2023	In-frame duplication of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This variant, c.1403_1408dup, results in the insertion of 2 amino acid(s) of the DOK7 protein (p.Gly468_Pro469dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762148551, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 639843). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs762148551; hg19: chr4-3495111;