4-3485625-A-G

Variant names:

• chr4-3485625-A-G
• rs1240579533
• NM_173660.5:c.619A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173660.5(DOK7):​c.619A>G​(p.Lys207Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,452,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. K207Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39057583).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.619A>G	p.Lys207Glu	missense	Exon 5 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.619A>G	p.Lys207Glu	missense	Exon 5 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.187A>G	p.Lys63Glu	missense	Exon 3 of 8	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.619A>G	p.Lys207Glu	missense	Exon 5 of 7	ENSP00000344432.5
	DOK7	ENST00000513995.1	TSL:1	n.277A>G		non_coding_transcript_exon	Exon 1 of 3
	DOK7	ENST00000643608.1		c.187A>G	p.Lys63Glu	missense	Exon 3 of 8	ENSP00000495701.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 242328 AF XY: 0.00000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452866 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 722566

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 38972

South Asian (SAS) AF: 0.00 AC: 0 AN: 85032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107564

Other (OTH) AF: 0.0000167 AC: 1 AN: 59972

GnomAD4 genome Cov.: 34

EpiCase AF: 0.00

EpiControl AF: 0.0000604

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.18	D
PhyloP100		3.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.017	D
Polyphen		0.26	B
Vest4		0.53
MutPred		0.36		Loss of ubiquitination at K207 (P = 0.011)
MVP		0.82
MPC		0.0059
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.58
gMVP		0.48
Mutation Taster		=75/25	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: rs1240579533; hg19: chr4-3487352;