NM_173660.5:c.1403_1408dupGCCCTG

Variant names:

• chr4-3493384-G-GCCTGGC
• rs762148551
• NM_173660.5:c.1403_1408dupGCCCTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A470A) has been classified as Likely benign.

• 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.660
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_173660.5.

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.1403_1408dupGCCCTG	p.Gly468_Pro469dup	disruptive_inframe_insertion	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1403_1408dupGCCCTG	p.Gly468_Pro469dup	disruptive_inframe_insertion	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.971_976dupGCCCTG	p.Gly324_Pro325dup	disruptive_inframe_insertion	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.1403_1408dupGCCCTG	p.Gly468_Pro469dup	disruptive_inframe_insertion	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.971_976dupGCCCTG	p.Gly324_Pro325dup	disruptive_inframe_insertion	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000515886.5	TSL:2	c.473_478dupGCCCTG	p.Gly158_Pro159dup	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

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

GnomAD2 exomes AF: 0.000295 AC: 59 AN: 200306 AF XY: 0.000307

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 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

African (AFR) AF: 0.0000301 AC: 1 AN: 33188

American (AMR) AF: 0.000239 AC: 10 AN: 41800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38872

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84124

European-Finnish (FIN) AF: 0.0000399 AC: 2 AN: 50124

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5642

European-Non Finnish (NFE) AF: 0.000711 AC: 784 AN: 1103034

Other (OTH) AF: 0.000453 AC: 27 AN: 59544

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.000327 AC: 5 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000283

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	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
PhyloP100		0.66
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs762148551; hg19: chr4-3495111;