4-3492867-C-G

Variant names:

• chr4-3492867-C-G
• rs151079259
• NM_173660.5:c.881C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173660.5(DOK7):​c.881C>G​(p.Thr294Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T294M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26179904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.881C>G	p.Thr294Arg	missense_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.881C>G	p.Thr294Arg	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455728 Hom.: 0 Cov.: 98 AF XY: 0.00 AC XY: 0 AN XY: 723828

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110360

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	M;.
PhyloP100		3.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.16
Sift	Benign	0.031	D;.
Sift4G	Uncertain	0.013	D;.
Polyphen		0.88	P;.
Vest4		0.37
MutPred		0.23		Gain of glycosylation at T294 (P = 0.0155);.;
MVP		0.78
MPC		0.0079
ClinPred		0.52	D
GERP RS		2.8
Varity_R		0.26
gMVP		0.17
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151079259; hg19: chr4-3494594;