chr4-3463402-C-A

Variant names:

• chr4-3463402-C-A
• rs768798756
• NM_173660.5:c.27C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_173660.5(DOK7):​c.27C>A​(p.Gly9Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,318,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G9G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.363
• 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, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-3463402-C-A is Benign according to our data. Variant chr4-3463402-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1564482.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.363 with no splicing effect.

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.27C>A	p.Gly9Gly	synonymous	Exon 1 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.27C>A	p.Gly9Gly	synonymous	Exon 1 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.27C>A	p.Gly9Gly	synonymous	Exon 1 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.27C>A	p.Gly9Gly	synonymous	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.27C>A	p.Gly9Gly	synonymous	Exon 1 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.27C>A	p.Gly9Gly	synonymous	Exon 1 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.00000686 AC: 1 AN: 145670 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000692

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

GnomAD2 exomes AF: 0.0000709 AC: 8 AN: 112766 AF XY: 0.0000469

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000455 AC: 6 AN: 1318262 Hom.: 0 Cov.: 34 AF XY: 0.00000153 AC XY: 1 AN XY: 651680

African (AFR) AF: 0.00 AC: 0 AN: 26920

American (AMR) AF: 0.000244 AC: 6 AN: 24590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21356

East Asian (EAS) AF: 0.00 AC: 0 AN: 30592

South Asian (SAS) AF: 0.00 AC: 0 AN: 70814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1052548

Other (OTH) AF: 0.00 AC: 0 AN: 54140

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000686 AC: 1 AN: 145670 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 70732

African (AFR) AF: 0.00 AC: 0 AN: 39638

American (AMR) AF: 0.0000692 AC: 1 AN: 14444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4718

South Asian (SAS) AF: 0.00 AC: 0 AN: 4484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66540

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.95
PhyloP100		0.36
PromoterAI		-0.061	Neutral

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

Other links and lift over

dbSNP: rs768798756; hg19: chr4-3465129;