rs560463670

Positions:

• chr4-3493130-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):​c.1144G>A​(p.Glu382Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000353 in 1,595,634 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.02

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010363132).
• BP6: Variant 4-3493130-G-A is Benign according to our data. Variant chr4-3493130-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493130-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000256 (39/152316) while in subpopulation SAS AF= 0.00539 (26/4824). AF 95% confidence interval is 0.00378. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1144G>A	p.Glu382Lys	missense_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.1144G>A	p.Glu382Lys	missense_variant	7/7	1	NM_173660.5	ENSP00000344432	P1
DOK7	ENST00000643608.1	c.712G>A	p.Glu238Lys	missense_variant	5/8			ENSP00000495701
DOK7	ENST00000515886.5	c.214G>A	p.Glu72Lys	missense_variant	4/4	2		ENSP00000492194
DOK7	ENST00000507039.5	c.*365G>A		3_prime_UTR_variant	7/7	2		ENSP00000423614

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000745 AC: 156 AN: 209438 Hom.: 1 AF XY: 0.000840 AC XY: 97 AN XY: 115478

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.000662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000639

Gnomad SAS exome AF: 0.00427

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000871

Gnomad OTH exome AF: 0.000764

GnomAD4 exome AF: 0.000363 AC: 524 AN: 1443318 Hom.: 4 Cov.: 113 AF XY: 0.000455 AC XY: 326 AN XY: 717030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000421

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000486

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152316 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74488

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000894 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000677 AC: 81

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;.;.
Sift4G	Benign	0.12	T;.;.
Polyphen		0.65	P;.;.
Vest4		0.22
MVP		0.82
MPC		0.010
ClinPred		0.057	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.16

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: rs560463670; hg19: chr4-3494857;