chr4-3492904-C-T

Position:

• chr4-3492904-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001256896.2(DOK7):​c.-13C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000419 in 1,578,280 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: DOK7 NM_001256896.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.569

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-3492904-C-T is Benign according to our data. Variant chr4-3492904-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198627.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (212/152294) while in subpopulation AFR AF= 0.00327 (136/41576). AF 95% confidence interval is 0.00282. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.918C>T	p.Ala306Ala	synonymous_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.918C>T	p.Ala306Ala	synonymous_variant	7/7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152176 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000684 AC: 127 AN: 185582 Hom.: 0 AF XY: 0.000613 AC XY: 62 AN XY: 101150

Gnomad AFR exome AF: 0.00341

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000147

Gnomad SAS exome AF: 0.000116

Gnomad FIN exome AF: 0.00477

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000316 AC: 450 AN: 1425986 Hom.: 0 Cov.: 110 AF XY: 0.000324 AC XY: 229 AN XY: 706774

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.0000755

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.000240

Gnomad4 SAS exome AF: 0.000145

Gnomad4 FIN exome AF: 0.00374

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000440

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152294 Hom.: 0 Cov.: 34 AF XY: 0.00167 AC XY: 124 AN XY: 74458

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000718 Hom.: 0

Bravo AF: 0.00115

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.8
DANN	Benign	0.71

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

LitVar

Other links and lift over

dbSNP: rs141947707; hg19: chr4-3494631;