4-3493389-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173660.5(DOK7):c.1403G>C(p.Gly468Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. G468D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0884718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1403G>C	p.Gly468Ala	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1403G>C	p.Gly468Ala	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.971G>C	p.Gly324Ala	missense_variant	5/8
DOK7	ENST00000515886.5	c.473G>C	p.Gly158Ala	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*624G>C		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442532 Hom.: 0 Cov.: 88 AF XY: 0.00000140 AC XY: 1 AN XY: 716168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
Dann	Benign	0.091
DEOGEN2	Benign	0.046	T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.29	N;.;.
REVEL	Benign	0.080
Sift	Benign	0.55	T;.;.
Sift4G	Benign	0.32	T;.;.
Polyphen		0.0010	B;.;.
Vest4		0.12
MutPred		0.093		Gain of glycosylation at T465 (P = 0.0438);.;.;
MVP		0.65
MPC		0.0043
ClinPred		0.082	T
GERP RS		3.3
Varity_R		0.093
gMVP		0.075

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

Publications

LitVar

Other links and lift over

dbSNP: rs767909551; hg19: chr4-3495116;