rs59932476

Variant names:

• chr4-3489777-G-A
• rs59932476
• NM_173660.5:c.753G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3489777-G-A
• chr4-3489777-G-C
• chr4-3489777-G-T

Variant summary

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

The NM_001164673.2(DOK7):​c.742G>A​(p.Gly248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 1,572,772 control chromosomes in the GnomAD database, including 1,454 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G248W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.052 (291 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1163 hom.)
• Consequence: DOK7 NM_001164673.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.31
• Publications: 10 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 (MetaRNN=0.0018548965).
• BP6: Variant 4-3489777-G-A is Benign according to our data. Variant chr4-3489777-G-A is described in ClinVar as Benign. ClinVar VariationId is 128914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164673.2. 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.753G>A	p.Ala251Ala	synonymous	Exon 6 of 7	NP_775931.3
	DOK7	NM_001164673.2		c.742G>A	p.Gly248Arg	missense	Exon 6 of 7	NP_001158145.1	Q18PE1-4
	DOK7	NM_001301071.2		c.753G>A	p.Ala251Ala	synonymous	Exon 6 of 10	NP_001288000.1	Q18PE1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.753G>A	p.Ala251Ala	synonymous	Exon 6 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.411G>A		non_coding_transcript_exon	Exon 2 of 3
	DOK7	ENST00000507039.5	TSL:2	c.742G>A	p.Gly248Arg	missense	Exon 6 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7918 AN: 152002 Hom.: 289 Cov.: 32

Gnomad AFR AF: 0.0922

Gnomad AMI AF: 0.0771

Gnomad AMR AF: 0.0679

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0490 AC: 8993 AN: 183538 AF XY: 0.0471

Gnomad AFR exome AF: 0.0980

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.0380

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0482

GnomAD4 exome AF: 0.0361 AC: 51323 AN: 1420652 Hom.: 1163 Cov.: 32 AF XY: 0.0364 AC XY: 25577 AN XY: 702726

African (AFR) AF: 0.0912 AC: 2983 AN: 32712

American (AMR) AF: 0.0940 AC: 3686 AN: 39206

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 681 AN: 25352

East Asian (EAS) AF: 0.0207 AC: 776 AN: 37534

South Asian (SAS) AF: 0.0531 AC: 4297 AN: 80884

European-Finnish (FIN) AF: 0.0160 AC: 794 AN: 49540

Middle Eastern (MID) AF: 0.0553 AC: 316 AN: 5718

European-Non Finnish (NFE) AF: 0.0325 AC: 35438 AN: 1090902

Other (OTH) AF: 0.0400 AC: 2352 AN: 58804

GnomAD4 genome AF: 0.0521 AC: 7924 AN: 152120 Hom.: 291 Cov.: 32 AF XY: 0.0514 AC XY: 3821 AN XY: 74376

African (AFR) AF: 0.0921 AC: 3818 AN: 41476

American (AMR) AF: 0.0684 AC: 1047 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3472

East Asian (EAS) AF: 0.0313 AC: 162 AN: 5172

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4826

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10616

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2196 AN: 67950

Other (OTH) AF: 0.0393 AC: 83 AN: 2110

Alfa AF: 0.0368 Hom.: 341

Bravo AF: 0.0574

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.0877 AC: 382

ESP6500EA AF: 0.0321 AC: 275

ExAC AF: 0.0383 AC: 4520

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	0.60
DANN	Benign	0.57
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.49	T
PhyloP100		-2.3
PROVEAN	Benign	0.28	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Vest4		0.21
MutPred		0.13		Gain of MoRF binding (P = 0.0066)
ClinPred		0.0034	T
GERP RS		-1.9
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs59932476; hg19: chr4-3491504;