rs2344208

Variant names:

• chr4-3473380-G-A
• rs2344208
• NM_173660.5:c.101-26G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3473380-G-A
• chr4-3473380-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.101-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,607,292 control chromosomes in the GnomAD database, including 16,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2497 hom., cov: 34)
  • Exomes 𝑓: 0.14 (14471 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10
• Publications: 8 publications found

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]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-3473380-G-A is Benign according to our data. Variant chr4-3473380-G-A is described in ClinVar as Benign. ClinVar VariationId is 262864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.101-26G>A		intron_variant	Intron 2 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.101-26G>A		intron_variant	Intron 2 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25453 AN: 152094 Hom.: 2495 Cov.: 34

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0501

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.127 AC: 30058 AN: 237486 AF XY: 0.126

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0920

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0500

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.136 AC: 197318 AN: 1455080 Hom.: 14471 Cov.: 33 AF XY: 0.134 AC XY: 96940 AN XY: 723876

African (AFR) AF: 0.265 AC: 8825 AN: 33356

American (AMR) AF: 0.0981 AC: 4360 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4469 AN: 26060

East Asian (EAS) AF: 0.0327 AC: 1297 AN: 39612

South Asian (SAS) AF: 0.0714 AC: 6131 AN: 85858

European-Finnish (FIN) AF: 0.105 AC: 5415 AN: 51576

Middle Eastern (MID) AF: 0.209 AC: 862 AN: 4134

European-Non Finnish (NFE) AF: 0.142 AC: 157441 AN: 1110002

Other (OTH) AF: 0.142 AC: 8518 AN: 60026

GnomAD4 genome AF: 0.167 AC: 25476 AN: 152212 Hom.: 2497 Cov.: 34 AF XY: 0.163 AC XY: 12138 AN XY: 74414

African (AFR) AF: 0.261 AC: 10845 AN: 41526

American (AMR) AF: 0.140 AC: 2137 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.0500 AC: 259 AN: 5176

South Asian (SAS) AF: 0.0640 AC: 309 AN: 4828

European-Finnish (FIN) AF: 0.101 AC: 1067 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9718 AN: 67990

Other (OTH) AF: 0.183 AC: 386 AN: 2112

Alfa AF: 0.100 Hom.: 173

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.74
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2344208; hg19: chr4-3475107;