rs6811856

Variant names:

• chr4-3493099-A-C
• rs6811856
• NM_173660.5:c.1113A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-3493099-A-C
• chr4-3493099-A-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173660.5(DOK7):​c.1113A>C​(p.Ser371Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,579,746 control chromosomes in the GnomAD database, including 40,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3574 hom., cov: 34)
  • Exomes 𝑓: 0.22 (36706 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.44
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 4-3493099-A-C is Benign according to our data. Variant chr4-3493099-A-C is described in ClinVar as Benign. ClinVar VariationId is 128904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

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.1113A>C	p.Ser371Ser	synonymous	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1113A>C	p.Ser371Ser	synonymous	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.681A>C	p.Ser227Ser	synonymous	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.1113A>C	p.Ser371Ser	synonymous	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.681A>C	p.Ser227Ser	synonymous	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000515886.5	TSL:2	c.183A>C	p.Ser61Ser	synonymous	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28587 AN: 152040 Hom.: 3579 Cov.: 34

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.224 AC: 42420 AN: 189222 AF XY: 0.227

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.489

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.217 AC: 309943 AN: 1427588 Hom.: 36706 Cov.: 110 AF XY: 0.217 AC XY: 154015 AN XY: 708228

African (AFR) AF: 0.0481 AC: 1584 AN: 32950

American (AMR) AF: 0.143 AC: 5810 AN: 40532

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5676 AN: 25624

East Asian (EAS) AF: 0.507 AC: 19129 AN: 37738

South Asian (SAS) AF: 0.209 AC: 17299 AN: 82722

European-Finnish (FIN) AF: 0.381 AC: 16812 AN: 44122

Middle Eastern (MID) AF: 0.148 AC: 850 AN: 5742

European-Non Finnish (NFE) AF: 0.209 AC: 229974 AN: 1098934

Other (OTH) AF: 0.216 AC: 12809 AN: 59224

GnomAD4 genome AF: 0.188 AC: 28585 AN: 152158 Hom.: 3574 Cov.: 34 AF XY: 0.195 AC XY: 14505 AN XY: 74388

African (AFR) AF: 0.0556 AC: 2310 AN: 41546

American (AMR) AF: 0.152 AC: 2330 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 731 AN: 3470

East Asian (EAS) AF: 0.514 AC: 2649 AN: 5158

South Asian (SAS) AF: 0.226 AC: 1091 AN: 4830

European-Finnish (FIN) AF: 0.385 AC: 4073 AN: 10570

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14692 AN: 67970

Other (OTH) AF: 0.191 AC: 402 AN: 2110

Alfa AF: 0.190 Hom.: 2900

Bravo AF: 0.166

Asia WGS AF: 0.366 AC: 1273 AN: 3476

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
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.38
DANN	Benign	0.59
PhyloP100		-4.4
Mutation Taster		=99/1	polymorphism (auto)

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: rs6811856; hg19: chr4-3494826; COSMIC: COSV60772560; COSMIC: COSV60772560;