rs370039804

Positions:

• chr4-3493191-G-A
• chr4-3493191-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_173660.5(DOK7):​c.1205G>A​(p.Arg402Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000708 in 1,610,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.43

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14910758).
• BP6: Variant 4-3493191-G-A is Benign according to our data. Variant chr4-3493191-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575016.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr4-3493191-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1205G>A	p.Arg402Gln	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1205G>A	p.Arg402Gln	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.773G>A	p.Arg258Gln	missense_variant	5/8
DOK7	ENST00000515886.5	c.275G>A	p.Arg92Gln	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*426G>A		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000504 AC: 12 AN: 238324 Hom.: 0 AF XY: 0.0000383 AC XY: 5 AN XY: 130420

Gnomad AFR exome AF: 0.000270

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.0000474

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000514 AC: 75 AN: 1458582 Hom.: 0 Cov.: 97 AF XY: 0.0000496 AC XY: 36 AN XY: 725536

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152190 Hom.: 0 Cov.: 34 AF XY: 0.000350 AC XY: 26 AN XY: 74346

Gnomad4 AFR AF: 0.000869

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000668 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000829 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 22, 2019

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	0.0067
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	N;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.013	D;.;.
Sift4G	Benign	0.13	T;.;.
Polyphen		0.48	P;.;.
Vest4		0.51
MVP		0.76
MPC		0.015
ClinPred		0.21	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.45

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: rs370039804; hg19: chr4-3494918;