chr4-3492817-C-T

Position:

• chr4-3492817-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000340083.6(DOK7):​c.831C>T​(p.Ala277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,612,678 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (9 hom.)
• Consequence: DOK7 ENST00000340083.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.321

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 4-3492817-C-T is Benign according to our data. Variant chr4-3492817-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 465689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3492817-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00125 (190/152318) while in subpopulation SAS AF= 0.00373 (18/4822). AF 95% confidence interval is 0.00241. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.831C>T	p.Ala277=	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.831C>T	p.Ala277=	synonymous_variant	7/7	1	NM_173660.5	ENSP00000344432	P1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00165 AC: 408 AN: 247496 Hom.: 3 AF XY: 0.00192 AC XY: 258 AN XY: 134596

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00396

Gnomad FIN exome AF: 0.000793

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00160 AC: 2340 AN: 1460360 Hom.: 9 Cov.: 98 AF XY: 0.00170 AC XY: 1237 AN XY: 726504

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00390

Gnomad4 FIN exome AF: 0.000692

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.00118 AC XY: 88 AN XY: 74470

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00130

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	This variant is associated with the following publications: (PMID: 22661499) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DOK7: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 19, 2020

- -

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	-0.48
CADD	Benign	5.1
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150549589; hg19: chr4-3494544;