4-3476293-C-G

Variant names:

• chr4-3476293-C-G
• rs114112298
• NM_173660.5:c.332-49C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_173660.5(DOK7):​c.332-49C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 985,384 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (12 hom., cov: 23)
  • Exomes 𝑓: 0.00016 (23 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.315
• Publications: 2 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

LOC105374355 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0011 (132/119574) while in subpopulation AFR AF = 0.00385 (122/31660). AF 95% confidence interval is 0.0033. There are 12 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.332-49C>G		intron_variant	Intron 3 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.332-49C>G		intron_variant	Intron 3 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 126 AN: 119500 Hom.: 10 Cov.: 23

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000561

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00435

Gnomad NFE AF: 0.0000345

Gnomad OTH AF: 0.000632

GnomAD2 exomes AF: 0.000355 AC: 60 AN: 169116 AF XY: 0.000329

Gnomad AFR exome AF: 0.00533

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000252

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 141 AN: 865810 Hom.: 23 Cov.: 26 AF XY: 0.000153 AC XY: 67 AN XY: 438990

African (AFR) AF: 0.00560 AC: 117 AN: 20910

American (AMR) AF: 0.0000612 AC: 2 AN: 32660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15874

East Asian (EAS) AF: 0.00 AC: 0 AN: 17936

South Asian (SAS) AF: 0.00 AC: 0 AN: 70964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22856

Middle Eastern (MID) AF: 0.000273 AC: 1 AN: 3664

European-Non Finnish (NFE) AF: 0.00000463 AC: 3 AN: 647382

Other (OTH) AF: 0.000536 AC: 18 AN: 33564

GnomAD4 genome AF: 0.00110 AC: 132 AN: 119574 Hom.: 12 Cov.: 23 AF XY: 0.00106 AC XY: 60 AN XY: 56824

African (AFR) AF: 0.00385 AC: 122 AN: 31660

American (AMR) AF: 0.000560 AC: 6 AN: 10710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3078

East Asian (EAS) AF: 0.00 AC: 0 AN: 3732

South Asian (SAS) AF: 0.00 AC: 0 AN: 3272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6622

Middle Eastern (MID) AF: 0.00450 AC: 1 AN: 222

European-Non Finnish (NFE) AF: 0.0000345 AC: 2 AN: 57898

Other (OTH) AF: 0.000628 AC: 1 AN: 1592

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.5
DANN	Benign	0.64
PhyloP100		0.32
Mutation Taster		=100/0	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: rs114112298; hg19: chr4-3478020;