rs2344209

chr4-3473395-G-Achr4-3473395-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):c.101-11G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,609,870 control chromosomes in the GnomAD database, including 14,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1378 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13338 hom.)
• Consequence: DOK7 NM_173660.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002856
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.14

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 (BayesDel_noAF=-0.79).
• BP6: Variant 4-3473395-G-A is Benign according to our data. Variant chr4-3473395-G-A is described in ClinVar as [Benign]. Clinvar id is 262863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3473395-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.101-11G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.101-11G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19663 AN: 152148 Hom.: 1378 Cov.: 34

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0497

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.116 AC: 28051 AN: 242096 Hom.: 1904 AF XY: 0.117 AC XY: 15573 AN XY: 132770

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0498

Gnomad SAS exome AF: 0.0721

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.131 AC: 191339 AN: 1457604 Hom.: 13338 Cov.: 34 AF XY: 0.130 AC XY: 94313 AN XY: 725132

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.0890

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.0328

Gnomad4 SAS exome AF: 0.0710

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.129 AC: 19674 AN: 152266 Hom.: 1378 Cov.: 34 AF XY: 0.127 AC XY: 9476 AN XY: 74456

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0496

Gnomad4 SAS AF: 0.0638

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.158

Alfa AF: 0.137 Hom.: 285

Bravo AF: 0.133

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2016	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	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.7
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.022
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: rs2344209; hg19: chr4-3475122;