4-3493130-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_173660.5(DOK7):​c.1144G>T​(p.Glu382*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000693 in 1,443,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DOK7
NM_173660.5 stop_gained

Scores

3
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.02
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOK7NM_173660.5 linkc.1144G>T p.Glu382* stop_gained Exon 7 of 7 ENST00000340083.6 NP_775931.3 Q18PE1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOK7ENST00000340083.6 linkc.1144G>T p.Glu382* stop_gained Exon 7 of 7 1 NM_173660.5 ENSP00000344432.5 Q18PE1-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443320
Hom.:
0
Cov.:
113
AF XY:
0.00
AC XY:
0
AN XY:
717032
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000209
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
54
DANN
Uncertain
0.99
Eigen
Pathogenic
0.78
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.78
D
Vest4
0.53
GERP RS
3.8

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-3494857; API