4-3492722-ACC-AC

Variant names:

• chr4-3492722-AC-A
• rs34230391
• NM_173660.5:c.773-32delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.773-32delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.36 (10320 hom., cov: 0)
  • Exomes 𝑓: 0.37 (100900 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.80
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 4-3492722-AC-A is Benign according to our data. Variant chr4-3492722-AC-A is described in ClinVar as Benign. ClinVar VariationId is 262889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 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.773-32delC		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.773-32delC		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.341-32delC		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.773-36delC		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.431-36delC		intron	N/A
	DOK7	ENST00000643608.1		c.341-36delC		intron	N/A	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54782 AN: 151288 Hom.: 10308 Cov.: 0

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.380 AC: 93011 AN: 244512 AF XY: 0.380

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.540

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.369 AC: 537596 AN: 1458134 Hom.: 100900 Cov.: 0 AF XY: 0.368 AC XY: 267140 AN XY: 725462

African (AFR) AF: 0.283 AC: 9458 AN: 33464

American (AMR) AF: 0.324 AC: 14499 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 10345 AN: 26116

East Asian (EAS) AF: 0.534 AC: 21179 AN: 39690

South Asian (SAS) AF: 0.337 AC: 29066 AN: 86222

European-Finnish (FIN) AF: 0.495 AC: 24814 AN: 50118

Middle Eastern (MID) AF: 0.370 AC: 2127 AN: 5752

European-Non Finnish (NFE) AF: 0.363 AC: 403721 AN: 1111744

Other (OTH) AF: 0.371 AC: 22387 AN: 60344

GnomAD4 genome AF: 0.362 AC: 54829 AN: 151408 Hom.: 10320 Cov.: 0 AF XY: 0.365 AC XY: 27014 AN XY: 74006

African (AFR) AF: 0.299 AC: 12236 AN: 40978

American (AMR) AF: 0.336 AC: 5118 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1330 AN: 3472

East Asian (EAS) AF: 0.550 AC: 2833 AN: 5152

South Asian (SAS) AF: 0.350 AC: 1685 AN: 4810

European-Finnish (FIN) AF: 0.491 AC: 5192 AN: 10568

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25019 AN: 67866

Other (OTH) AF: 0.378 AC: 796 AN: 2106

Alfa AF: 0.364 Hom.: 1844

Bravo AF: 0.351

Asia WGS AF: 0.477 AC: 1659 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34230391; hg19: chr4-3494449;