4-3463423-C-G

Variant names:

• chr4-3463423-C-G
• NM_173660.5:c.48C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_173660.5(DOK7):​c.48C>G​(p.Gly16Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.305
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 4-3463423-C-G is Benign according to our data. Variant chr4-3463423-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2947046.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.305 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.48C>G	p.Gly16Gly	synonymous	Exon 1 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.48C>G	p.Gly16Gly	synonymous	Exon 1 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.48C>G	p.Gly16Gly	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.48C>G	p.Gly16Gly	synonymous	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.48C>G	p.Gly16Gly	synonymous	Exon 1 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.48C>G	p.Gly16Gly	synonymous	Exon 1 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.34e-7 AC: 1 AN: 1070738 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 529640

African (AFR) AF: 0.00 AC: 0 AN: 23926

American (AMR) AF: 0.00 AC: 0 AN: 20136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17822

East Asian (EAS) AF: 0.00 AC: 0 AN: 21972

South Asian (SAS) AF: 0.0000157 AC: 1 AN: 63580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3084

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 849618

Other (OTH) AF: 0.00 AC: 0 AN: 43816

GnomAD4 genome Cov.: 29

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
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		0.30
PromoterAI		0.039	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

hg19: chr4-3465150;