NM_173660.5:c.638G>C

Variant names:

• chr4-3485644-G-C
• rs371408752
• NM_173660.5:c.638G>C

Variant summary

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

The NM_173660.5(DOK7):​c.638G>C​(p.Arg213Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.638G>C	p.Arg213Pro	missense	Exon 5 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.638G>C	p.Arg213Pro	missense	Exon 5 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.206G>C	p.Arg69Pro	missense	Exon 3 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.638G>C	p.Arg213Pro	missense	Exon 5 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.296G>C		non_coding_transcript_exon	Exon 1 of 3
	DOK7	ENST00000643608.1		c.206G>C	p.Arg69Pro	missense	Exon 3 of 8	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448216 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719994

African (AFR) AF: 0.00 AC: 0 AN: 32928

American (AMR) AF: 0.00 AC: 0 AN: 43712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 38710

South Asian (SAS) AF: 0.00 AC: 0 AN: 84306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105160

Other (OTH) AF: 0.00 AC: 0 AN: 59774

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.17	D
PhyloP100		4.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.59
MutPred		0.33		Loss of glycosylation at P217 (P = 0.02)
MVP		0.87
MPC		0.014
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.87
gMVP		0.64
Mutation Taster		=70/30	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: rs371408752; hg19: chr4-3487371; COSMIC: COSV60772808;