4-3492904-C-T

Position:

• chr4-3492904-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The ENST00000340083.6(DOK7):​c.918C>T​(p.Ala306=) variant causes a synonymous 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). Synonymous variant affecting the same amino acid position (i.e. A306A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: DOK7 ENST00000340083.6 synonymous
• 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]

ACMG classification

Verdict is Benign. Variant got -8 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: {Benign=1, Uncertain_significance=1, Likely_benign=2}.
• BP7: Synonymous conserved (PhyloP=-0.569 with no splicing effect.
• 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.Ala306=	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.Ala306=	synonymous_variant	7/7	1	NM_173660.5	ENSP00000344432	P1

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;