4-3493264-C-T

Position:

• chr4-3493264-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_173660.5(DOK7):​c.1278C>T​(p.Pro426=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,611,556 control chromosomes in the GnomAD database, including 9 homozygotes. 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. P426P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.92

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-3493264-C-T is Benign according to our data. Variant chr4-3493264-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281424.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00174 (265/152346) while in subpopulation NFE AF= 0.00295 (201/68026). AF 95% confidence interval is 0.00262. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1278C>T	p.Pro426=	synonymous_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1278C>T	p.Pro426=	synonymous_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.846C>T	p.Pro282=	synonymous_variant	5/8
DOK7	ENST00000515886.5	c.348C>T	p.Pro116=	synonymous_variant	4/4	2
DOK7	ENST00000507039.5	c.*499C>T		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152228 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00180 AC: 423 AN: 235508 Hom.: 3 AF XY: 0.00181 AC XY: 235 AN XY: 129518

Gnomad AFR exome AF: 0.000488

Gnomad AMR exome AF: 0.000910

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0000991

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00259 AC: 3781 AN: 1459210 Hom.: 8 Cov.: 96 AF XY: 0.00249 AC XY: 1804 AN XY: 725846

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000874

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00274

Gnomad4 NFE exome AF: 0.00311

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152346 Hom.: 1 Cov.: 34 AF XY: 0.00169 AC XY: 126 AN XY: 74492

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00187

EpiCase AF: 0.00284

EpiControl AF: 0.00196

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)	Jun 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DOK7: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 19, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.65

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: rs139468087; hg19: chr4-3494991; COSMIC: COSV100403634; COSMIC: COSV100403634;