rs16844470

Variant names:

• chr4-3493337-C-T
• rs16844470
• NM_173660.5:c.1351C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-3493337-C-T
• chr4-3493337-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):​c.1351C>T​(p.Arg451Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,600,082 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (45 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.02
• Publications: 4 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=0.0030781329).
• BP6: Variant 4-3493337-C-T is Benign according to our data. Variant chr4-3493337-C-T is described in ClinVar as Benign. ClinVar VariationId is 128910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2052/152308) while in subpopulation AFR AF = 0.0432 (1798/41578). AF 95% confidence interval is 0.0416. There are 34 homozygotes in GnomAd4. There are 944 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.1351C>T	p.Arg451Trp	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1351C>T	p.Arg451Trp	missense	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.919C>T	p.Arg307Trp	missense	Exon 5 of 8	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.1351C>T	p.Arg451Trp	missense	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.919C>T	p.Arg307Trp	missense	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000515886.5	TSL:2	c.421C>T	p.Arg141Trp	missense	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2048 AN: 152190 Hom.: 34 Cov.: 34

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00362 AC: 773 AN: 213460 AF XY: 0.00309

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.000998

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00219 AC: 3165 AN: 1447774 Hom.: 45 Cov.: 96 AF XY: 0.00210 AC XY: 1510 AN XY: 718856

African (AFR) AF: 0.0404 AC: 1341 AN: 33190

American (AMR) AF: 0.00413 AC: 178 AN: 43098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39138

South Asian (SAS) AF: 0.000507 AC: 43 AN: 84886

European-Finnish (FIN) AF: 0.0000592 AC: 3 AN: 50694

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5740

European-Non Finnish (NFE) AF: 0.00123 AC: 1359 AN: 1105618

Other (OTH) AF: 0.00385 AC: 230 AN: 59712

GnomAD4 genome AF: 0.0135 AC: 2052 AN: 152308 Hom.: 34 Cov.: 34 AF XY: 0.0127 AC XY: 944 AN XY: 74474

African (AFR) AF: 0.0432 AC: 1798 AN: 41578

American (AMR) AF: 0.00948 AC: 145 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68012

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00540 Hom.: 2

Bravo AF: 0.0152

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0409 AC: 173

ESP6500EA AF: 0.00132 AC: 11

ExAC AF: 0.00371 AC: 437

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.021	D
Polyphen		0.27	B
Vest4		0.32
MVP		0.77
MPC		0.019
ClinPred		0.024	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.15
Mutation Taster		=98/2	polymorphism

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: rs16844470; hg19: chr4-3495064;