rs16844460

chr4-3492768-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):c.782G>A(p.Arg261His) variant causes a missense change. The variant allele was found at a frequency of 0.00188 in 1,612,562 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R261G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (28 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.65

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006664932).
• BP6: Variant 4-3492768-G-A is Benign according to our data. Variant chr4-3492768-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3492768-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00982 (1495/152246) while in subpopulation AFR AF= 0.0346 (1437/41508). AF 95% confidence interval is 0.0331. There are 28 homozygotes in gnomad4. There are 710 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.782G>A	p.Arg261His	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.782G>A	p.Arg261His	missense_variant	7/7	1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 1494 AN: 152128 Hom.: 28 Cov.: 34

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00268 AC: 662 AN: 247404 Hom.: 7 AF XY: 0.00183 AC XY: 246 AN XY: 134546

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00106 AC: 1541 AN: 1460316 Hom.: 27 Cov.: 97 AF XY: 0.000847 AC XY: 615 AN XY: 726484

Gnomad4 AFR exome AF: 0.0397

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00982 AC: 1495 AN: 152246 Hom.: 28 Cov.: 34 AF XY: 0.00954 AC XY: 710 AN XY: 74436

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00182 Hom.: 6

Bravo AF: 0.0117

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00340 AC: 412

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.20
Sift	Benign	0.051	T;.
Sift4G	Uncertain	0.048	D;.
Polyphen		1.0	D;.
Vest4		0.46
MVP		0.82
MPC		0.017
ClinPred		0.032	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16844460; hg19: chr4-3494495;