NM_173660.5:c.54+26_54+27insAGGGG

Variant names:

• chr4-3463451-G-GGGGGA
• rs1553844254
• NM_173660.5:c.54+26_54+27insAGGGG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_173660.5(DOK7):​c.54+26_54+27insAGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.221
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 4-3463451-G-GGGGGA is Benign according to our data. Variant chr4-3463451-G-GGGGGA is described in ClinVar as Likely_benign. ClinVar VariationId is 534135.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000721 (5/69312) while in subpopulation AFR AF = 0.00514 (5/972). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

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.54+26_54+27insAGGGG		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.54+26_54+27insAGGGG		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.54+26_54+27insAGGGG		intron	N/A	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.54+22_54+23insGGGGA		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.54+22_54+23insGGGGA		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.54+22_54+23insGGGGA		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 4 AN: 14836 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000721 AC: 5 AN: 69312 Hom.: 0 Cov.: 0 AF XY: 0.0000303 AC XY: 1 AN XY: 32962

African (AFR) AF: 0.00514 AC: 5 AN: 972

American (AMR) AF: 0.00 AC: 0 AN: 768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 484

East Asian (EAS) AF: 0.00 AC: 0 AN: 2134

South Asian (SAS) AF: 0.00 AC: 0 AN: 1910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59280

Other (OTH) AF: 0.00 AC: 0 AN: 2580

GnomAD4 genome AF: 0.000270 AC: 4 AN: 14836 Hom.: 0 Cov.: 0 AF XY: 0.000292 AC XY: 2 AN XY: 6858

African (AFR) AF: 0.00112 AC: 4 AN: 3578

American (AMR) AF: 0.00 AC: 0 AN: 992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 472

East Asian (EAS) AF: 0.00 AC: 0 AN: 42

South Asian (SAS) AF: 0.00 AC: 0 AN: 362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8240

Other (OTH) AF: 0.00 AC: 0 AN: 182

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553844254; hg19: chr4-3465178;