rs547633164

Variant names:

• chr4-3493214-A-C
• rs547633164
• NM_173660.5:c.1228A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-3493214-A-C
• chr4-3493214-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173660.5(DOK7):​c.1228A>C​(p.Ser410Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S410G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.31
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.1228A>C	p.Ser410Arg	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1228A>C	p.Ser410Arg	missense	Exon 7 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.796A>C	p.Ser266Arg	missense	Exon 5 of 8	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1228A>C	p.Ser410Arg	missense	Exon 7 of 7	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.796A>C	p.Ser266Arg	missense	Exon 5 of 8	ENSP00000495701.1
	DOK7	ENST00000515886.5	TSL:2	c.298A>C	p.Ser100Arg	missense	Exon 4 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240218 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459636 Hom.: 0 Cov.: 97 AF XY: 0.00000275 AC XY: 2 AN XY: 726104

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000448 AC: 2 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.33
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.12	B
Vest4		0.65
MutPred		0.31		Gain of glycosylation at Y405 (P = 0.0118)
MVP		0.78
MPC		0.019
ClinPred		0.90	D
GERP RS		3.8
Varity_R		0.51
gMVP		0.43
Mutation Taster		=81/19	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: rs547633164; hg19: chr4-3494941;