rs150728781

Variant names:

• chr4-3492953-C-T
• rs150728781
• NM_173660.5:c.967C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-3492953-C-T
• chr4-3492953-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.967C>T​(p.Arg323Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,553,432 control chromosomes in the GnomAD database, including 33 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. R323H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0076 (20 hom., cov: 34)
  • Exomes 𝑓: 0.00082 (13 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.35
• Publications: 6 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=0.0067362487).
• BP6: Variant 4-3492953-C-T is Benign according to our data. Variant chr4-3492953-C-T is described in ClinVar as Benign. ClinVar VariationId is 128917.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 = 0.00765 (1165/152338) while in subpopulation AFR AF = 0.0269 (1117/41582). AF 95% confidence interval is 0.0256. There are 20 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.967C>T	p.Arg323Cys	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.967C>T	p.Arg323Cys	missense	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.535C>T	p.Arg179Cys	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.967C>T	p.Arg323Cys	missense	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.535C>T	p.Arg179Cys	missense	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000515886.5	TSL:2	c.37C>T	p.Arg13Cys	missense	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1164 AN: 152220 Hom.: 20 Cov.: 34

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00185 AC: 283 AN: 153362 AF XY: 0.00146

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.000979

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000172

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000908

GnomAD4 exome AF: 0.000821 AC: 1150 AN: 1401094 Hom.: 13 Cov.: 111 AF XY: 0.000702 AC XY: 486 AN XY: 692378

African (AFR) AF: 0.0290 AC: 932 AN: 32120

American (AMR) AF: 0.00120 AC: 44 AN: 36714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25224

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36382

South Asian (SAS) AF: 0.0000745 AC: 6 AN: 80516

European-Finnish (FIN) AF: 0.0000475 AC: 2 AN: 42096

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5708

European-Non Finnish (NFE) AF: 0.0000480 AC: 52 AN: 1084106

Other (OTH) AF: 0.00189 AC: 110 AN: 58228

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152338 Hom.: 20 Cov.: 34 AF XY: 0.00728 AC XY: 542 AN XY: 74482

African (AFR) AF: 0.0269 AC: 1117 AN: 41582

American (AMR) AF: 0.00203 AC: 31 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00879

ESP6500AA AF: 0.0231 AC: 93

ESP6500EA AF: 0.000125 AC: 1

ExAC AF: 0.00148 AC: 169

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.092
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.19
Sift	Benign	0.088	T
Sift4G	Benign	0.068	T
Polyphen		0.97	D
Vest4		0.58
MVP		0.75
MPC		0.0092
ClinPred		0.020	T
GERP RS		4.1
Varity_R		0.24
gMVP		0.12
Mutation Taster		=94/6	polymorphism

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: rs150728781; hg19: chr4-3494680; COSMIC: COSV106103977; COSMIC: COSV106103977;