rs184556570

Variant names:

• chr4-3493493-C-A
• rs184556570
• NM_173660.5:c.1507C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3493493-C-A
• chr4-3493493-C-G
• chr4-3493493-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173660.5(DOK7):​c.1507C>A​(p.Pro503Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,611,192 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00068 (6 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.875
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007641524).
• BP6: Variant 4-3493493-C-A is Benign according to our data. Variant chr4-3493493-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465680.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000518 (79/152372) while in subpopulation SAS AF = 0.00311 (15/4830). AF 95% confidence interval is 0.00191. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1507C>A	p.Pro503Thr	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001256896.2		c.577C>A	p.Pro193Thr	missense	Exon 4 of 4	NP_001243825.1	A0A1W2PRA3
	DOK7	NM_001164673.2		c.*728C>A		3_prime_UTR	Exon 7 of 7	NP_001158145.1	Q18PE1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1507C>A	p.Pro503Thr	missense	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000515886.5	TSL:2	c.577C>A	p.Pro193Thr	missense	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3
	DOK7	ENST00000507039.5	TSL:2	c.*728C>A		3_prime_UTR	Exon 7 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152254 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00117 AC: 277 AN: 236896 AF XY: 0.00151

Gnomad AFR exome AF: 0.0000717

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00207

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000283

Gnomad NFE exome AF: 0.000768

Gnomad OTH exome AF: 0.000856

GnomAD4 exome AF: 0.000681 AC: 993 AN: 1458820 Hom.: 6 Cov.: 88 AF XY: 0.000845 AC XY: 613 AN XY: 725558

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.000852 AC: 38 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00430 AC: 370 AN: 85990

European-Finnish (FIN) AF: 0.000251 AC: 13 AN: 51754

Middle Eastern (MID) AF: 0.00491 AC: 28 AN: 5708

European-Non Finnish (NFE) AF: 0.000400 AC: 444 AN: 1111318

Other (OTH) AF: 0.000996 AC: 60 AN: 60252

GnomAD4 genome AF: 0.000518 AC: 79 AN: 152372 Hom.: 1 Cov.: 35 AF XY: 0.000537 AC XY: 40 AN XY: 74510

African (AFR) AF: 0.000120 AC: 5 AN: 41594

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

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

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.00113 AC: 136

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital myasthenic syndrome 10 (1)
-	-	1	Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 (1)
-	-	1	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.88
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.097
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.063	T
Polyphen		0.95	P
Vest4		0.29
MVP		0.69
MPC		0.019
ClinPred		0.031	T
GERP RS		3.6
Varity_R		0.22
gMVP		0.093
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: rs184556570; hg19: chr4-3495220;