rs191981243

Positions:

• chr4-3489658-A-C
• chr4-3489658-A-G

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.653-19A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,562,800 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 32)
  • Exomes 𝑓: 0.018 (302 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.598

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: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-3489658-A-C is Benign according to our data. Variant chr4-3489658-A-C is described in ClinVar as [Benign]. Clinvar id is 262885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3489658-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1824/152154) while in subpopulation NFE AF= 0.0173 (1176/67962). AF 95% confidence interval is 0.0165. There are 13 homozygotes in gnomad4. There are 870 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.653-19A>C		intron_variant		ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.653-19A>C		intron_variant		1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1826 AN: 152036 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0120 AC: 2052 AN: 171388 Hom.: 11 AF XY: 0.0116 AC XY: 1060 AN XY: 91504

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.0000784

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0179 AC: 25211 AN: 1410646 Hom.: 302 Cov.: 32 AF XY: 0.0173 AC XY: 12067 AN XY: 697188

Gnomad4 AFR exome AF: 0.00286

Gnomad4 AMR exome AF: 0.00882

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.0000547

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0120 AC: 1824 AN: 152154 Hom.: 13 Cov.: 32 AF XY: 0.0117 AC XY: 870 AN XY: 74372

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0150 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.6
DANN	Benign	0.46
BranchPoint Hunter		3.0

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: rs191981243; hg19: chr4-3491385;