NM_173660.5:c.893G>C

Variant names:

• chr4-3492879-G-C
• rs1553850025
• NM_173660.5:c.893G>C

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.893G>C​(p.Gly298Ala) variant causes a missense 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. 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. G298E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• 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: 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=0.24558687).

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.893G>C	p.Gly298Ala	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.893G>C	p.Gly298Ala	missense	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.461G>C	p.Gly154Ala	missense	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.893G>C	p.Gly298Ala	missense	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.551G>C		non_coding_transcript_exon	Exon 3 of 3
	DOK7	ENST00000643608.1		c.461G>C	p.Gly154Ala	missense	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 111

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.039	D
Sift4G	Benign	0.38	T
Polyphen		0.13	B
Vest4		0.13
MutPred		0.15		Gain of glycosylation at T294 (P = 0.0155)
MVP		0.76
MPC		0.013
ClinPred		0.68	D
GERP RS		3.9
Varity_R		0.17
gMVP		0.085
Mutation Taster		=82/18	polymorphism

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: rs1553850025; hg19: chr4-3494606;