4-3476324-T-C

Variant names:

• chr4-3476324-T-C
• rs2699425
• NM_173660.5:c.332-18T>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.332-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 775,664 control chromosomes in the GnomAD database, including 27,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5709 hom., cov: 17)
  • Exomes 𝑓: 0.14 (22216 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.50
• 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

LOC105374355 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-3476324-T-C is Benign according to our data. Variant chr4-3476324-T-C is described in ClinVar as Benign. ClinVar VariationId is 262875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.332-18T>C		intron_variant	Intron 3 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.332-18T>C		intron_variant	Intron 3 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.283 AC: 25727 AN: 91024 Hom.: 5697 Cov.: 17

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.0787

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.0321 AC: 3026 AN: 94144 AF XY: 0.0289

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.0429

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.0198

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.140 AC: 96084 AN: 684598 Hom.: 22216 Cov.: 35 AF XY: 0.145 AC XY: 49720 AN XY: 342088

African (AFR) AF: 0.240 AC: 2761 AN: 11522

American (AMR) AF: 0.324 AC: 7731 AN: 23838

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 1575 AN: 11692

East Asian (EAS) AF: 0.237 AC: 5979 AN: 25240

South Asian (SAS) AF: 0.234 AC: 9902 AN: 42316

European-Finnish (FIN) AF: 0.136 AC: 3820 AN: 28106

Middle Eastern (MID) AF: 0.150 AC: 382 AN: 2544

European-Non Finnish (NFE) AF: 0.117 AC: 60116 AN: 511864

Other (OTH) AF: 0.139 AC: 3818 AN: 27476

GnomAD4 genome AF: 0.283 AC: 25759 AN: 91066 Hom.: 5709 Cov.: 17 AF XY: 0.284 AC XY: 12591 AN XY: 44320

African (AFR) AF: 0.351 AC: 7330 AN: 20910

American (AMR) AF: 0.327 AC: 2948 AN: 9026

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 461 AN: 2022

East Asian (EAS) AF: 0.269 AC: 1106 AN: 4110

South Asian (SAS) AF: 0.266 AC: 669 AN: 2516

European-Finnish (FIN) AF: 0.199 AC: 1387 AN: 6962

Middle Eastern (MID) AF: 0.307 AC: 54 AN: 176

European-Non Finnish (NFE) AF: 0.261 AC: 11384 AN: 43544

Other (OTH) AF: 0.305 AC: 375 AN: 1228

Alfa AF: 0.404 Hom.: 2888

Bravo AF: 0.425

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2016

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. -

Congenital myasthenic syndrome 10 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fetal akinesia deformation sequence 3 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.51
DANN	Benign	0.38
PhyloP100		-2.5
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: rs2699425; hg19: chr4-3478051; COSMIC: COSV60773813;