rs2344209

Variant names:

• chr4-3473395-G-A
• rs2344209
• NM_173660.5:c.101-11G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3473395-G-A
• chr4-3473395-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.101-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,609,870 control chromosomes in the GnomAD database, including 14,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1378 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13338 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Scores: Splicing: ADA: 0.0002856
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.14
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-3473395-G-A is Benign according to our data. Variant chr4-3473395-G-A is described in ClinVar as Benign. ClinVar VariationId is 262863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.101-11G>A		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.101-11G>A		intron	N/A	NP_001288000.1
	DOK7	NM_001363811.2		c.100+9844G>A		intron	N/A	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.101-11G>A		intron	N/A	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.100+9844G>A		intron	N/A	ENSP00000495701.1
	DOK7	ENST00000507039.5	TSL:2	c.101-11G>A		intron	N/A	ENSP00000423614.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19663 AN: 152148 Hom.: 1378 Cov.: 34

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0497

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.116 AC: 28051 AN: 242096 AF XY: 0.117

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0498

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.131 AC: 191339 AN: 1457604 Hom.: 13338 Cov.: 34 AF XY: 0.130 AC XY: 94313 AN XY: 725132

African (AFR) AF: 0.129 AC: 4312 AN: 33398

American (AMR) AF: 0.0890 AC: 3974 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4475 AN: 26102

East Asian (EAS) AF: 0.0328 AC: 1300 AN: 39672

South Asian (SAS) AF: 0.0710 AC: 6112 AN: 86086

European-Finnish (FIN) AF: 0.105 AC: 5472 AN: 52072

Middle Eastern (MID) AF: 0.199 AC: 822 AN: 4140

European-Non Finnish (NFE) AF: 0.141 AC: 156898 AN: 1111340

Other (OTH) AF: 0.133 AC: 7974 AN: 60138

GnomAD4 genome AF: 0.129 AC: 19674 AN: 152266 Hom.: 1378 Cov.: 34 AF XY: 0.127 AC XY: 9476 AN XY: 74456

African (AFR) AF: 0.130 AC: 5390 AN: 41552

American (AMR) AF: 0.125 AC: 1905 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3470

East Asian (EAS) AF: 0.0496 AC: 257 AN: 5182

South Asian (SAS) AF: 0.0638 AC: 308 AN: 4830

European-Finnish (FIN) AF: 0.101 AC: 1068 AN: 10620

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9659 AN: 68000

Other (OTH) AF: 0.158 AC: 334 AN: 2112

Alfa AF: 0.137 Hom.: 285

Bravo AF: 0.133

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	-0.79
CADD	Benign	7.7
DANN	Benign	0.82
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.022
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: rs2344209; hg19: chr4-3475122;