4-3473380-G-C

Variant names:

• chr4-3473380-G-C
• rs2344208
• NM_173660.5:c.101-26G>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>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,607,178 control chromosomes in the GnomAD database, including 26,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5174 hom., cov: 34)
  • Exomes 𝑓: 0.16 (21098 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.94).
• BP6: Variant 4-3473380-G-C is Benign according to our data. Variant chr4-3473380-G-C is described in ClinVar as Benign. ClinVar VariationId is 262865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.101-26G>C		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.101-26G>C		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.100+9829G>C		intron	N/A	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.101-26G>C		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.100+9829G>C		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.101-26G>C		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35230 AN: 152088 Hom.: 5157 Cov.: 34

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.197 AC: 46805 AN: 237486 AF XY: 0.186

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.297

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.158 AC: 230210 AN: 1454972 Hom.: 21098 Cov.: 33 AF XY: 0.157 AC XY: 113621 AN XY: 723782

African (AFR) AF: 0.428 AC: 14273 AN: 33354

American (AMR) AF: 0.307 AC: 13629 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2852 AN: 26058

East Asian (EAS) AF: 0.317 AC: 12573 AN: 39606

South Asian (SAS) AF: 0.161 AC: 13847 AN: 85826

European-Finnish (FIN) AF: 0.130 AC: 6683 AN: 51564

Middle Eastern (MID) AF: 0.183 AC: 757 AN: 4134

European-Non Finnish (NFE) AF: 0.140 AC: 155549 AN: 1109960

Other (OTH) AF: 0.167 AC: 10047 AN: 60024

GnomAD4 genome AF: 0.232 AC: 35285 AN: 152206 Hom.: 5174 Cov.: 34 AF XY: 0.231 AC XY: 17207 AN XY: 74404

African (AFR) AF: 0.412 AC: 17116 AN: 41524

American (AMR) AF: 0.238 AC: 3639 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1521 AN: 5174

South Asian (SAS) AF: 0.162 AC: 783 AN: 4830

European-Finnish (FIN) AF: 0.133 AC: 1408 AN: 10600

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9897 AN: 67992

Other (OTH) AF: 0.200 AC: 423 AN: 2112

Alfa AF: 0.114 Hom.: 173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.074
DANN	Benign	0.29
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; COSMIC: COSV60773875;