4-3476523-C-T

Variant names:

• chr4-3476523-C-T
• rs775583136
• NM_173660.5:c.513C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_173660.5(DOK7):​c.513C>T​(p.Gly171Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.00900

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]

LOC105374355 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-3476523-C-T is Pathogenic according to our data. Variant chr4-3476523-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3476523-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.513C>T	p.Gly171Gly	synonymous_variant	Exon 4 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.513C>T	p.Gly171Gly	synonymous_variant	Exon 4 of 7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250616 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461598 Hom.: 0 Cov.: 39 AF XY: 0.0000179 AC XY: 13 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 Pathogenic:1

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 10 Pathogenic:1

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic mutation in a 13-year-old female with motor delays, hypotonia, neurogenic myopathy, fatigue, ptosis, joint contractures. The c.513C>T mutation, which does not affect amino acid translation, was shown to affect mRNA splicing in the literature. -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 171 of the DOK7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DOK7 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 7 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs775583136, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of congenital myasthenic syndrome (PMID: 22661499, 25326635; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429791). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 22661499). This variant disrupts the p.Gly172 amino acid residue in DOK7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20012313, 28716243, 30266093). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Fetal akinesia deformation sequence 3 Pathogenic:1

Feb 05, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 29, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in unknown phase with another pathogenic variant in multiple individuals with congenital myasthenic syndrome in the published literature or tested at GeneDx (Cossins et al., 2012; Burke et al., 2013; Yang et al., 2014); functional studies using exon trapping suggest that this variant causes an in-frame deletion of the last 7 amino acids in exon 4 of the DOK7 gene (Cossins et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20603078, 20012313, 22661499, 25326635, 23219351, 34831073) -

Congenital myasthenic syndrome Pathogenic:1

Aug 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DOK7 c.513C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates/strengthens a cryptic exonic 5' donor site. Experimental evidence supports these predictions demonstrating that this variant affects mRNA splicing, resulting in a truncated exon 4 lacking the last 21 nucleotides of the exon (Cossins_2012). The variant allele was found at a frequency of 8e-06 in 250616 control chromosomes. c.513C>T has been reported in the literature in compound heterozygous individuals affected with Congenital Myasthenic Syndrome (Cossins_2012, Yang_2014). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -2
DS_DL_spliceai		0.34		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775583136; hg19: chr4-3478250;