4-3493191-G-T

Variant names:

• chr4-3493191-G-T
• rs370039804
• NM_173660.5:c.1205G>T

Variant summary

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

The NM_173660.5(DOK7):​c.1205G>T​(p.Arg402Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R402Q) has been classified as Likely benign.

• 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: 2.43
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1205G>T	p.Arg402Leu	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.1205G>T	p.Arg402Leu	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1	c.773G>T	p.Arg258Leu	missense_variant	Exon 5 of 8			ENSP00000495701.1
DOK7	ENST00000515886.5	c.275G>T	p.Arg92Leu	missense_variant	Exon 4 of 4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*426G>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458582 Hom.: 0 Cov.: 97 AF XY: 0.00 AC XY: 0 AN XY: 725536

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111294

Other (OTH) AF: 0.00 AC: 0 AN: 60268

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	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.1	D;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.056	T;.;.
Sift4G	Benign	0.10	T;.;.
Polyphen		0.13	B;.;.
Vest4		0.40
MutPred		0.41		Loss of catalytic residue at R402 (P = 0.0082);.;.;
MVP		0.82
MPC		0.0095
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.33
gMVP		0.52
Mutation Taster		=92/8	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: rs370039804; hg19: chr4-3494918;