4-3492969-A-G

Variant summary

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

The NM_173660.5(DOK7):c.983A>G(p.Gln328Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000428 in 1,401,208 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. Q328P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.983A>G	p.Gln328Arg	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.983A>G	p.Gln328Arg	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.551A>G	p.Gln184Arg	missense_variant	5/8
DOK7	ENST00000515886.5	c.53A>G	p.Gln18Arg	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*204A>G		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1401208 Hom.: 0 Cov.: 111 AF XY: 0.00000722 AC XY: 5 AN XY: 692712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000369

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ExAC AF: 0.00000869 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2022

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 328 of the DOK7 protein (p.Gln328Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 571993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	0.026
Eigen_PC	Benign	0.0092
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.51	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.017	D;.;.
Sift4G	Uncertain	0.058	T;.;.
Polyphen		0.0020	B;.;.
Vest4		0.51
MutPred		0.27		Loss of glycosylation at P324 (P = 0.0157);.;.;
MVP		0.73
MPC		0.019
ClinPred		0.95	D
GERP RS		2.9
Varity_R		0.29
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752168445; hg19: chr4-3494696;