chr4-3493248-C-G

Position:

• chr4-3493248-C-G

Variant summary

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

The NM_173660.5(DOK7):​c.1262C>G​(p.Pro421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,611,954 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.669

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009750664).
• BP6: Variant 4-3493248-C-G is Benign according to our data. Variant chr4-3493248-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2056999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000134 (195/1459590) while in subpopulation SAS AF= 0.00188 (162/86176). AF 95% confidence interval is 0.00164. There are 1 homozygotes in gnomad4_exome. There are 143 alleles in male gnomad4_exome subpopulation. Median coverage is 97. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1262C>G	p.Pro421Arg	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.1262C>G	p.Pro421Arg	missense_variant	7/7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1	c.830C>G	p.Pro277Arg	missense_variant	5/8			ENSP00000495701.1
DOK7	ENST00000515886.5	c.332C>G	p.Pro111Arg	missense_variant	4/4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*483C>G		3_prime_UTR_variant	7/7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000227 AC: 54 AN: 237536 Hom.: 0 AF XY: 0.000352 AC XY: 46 AN XY: 130538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000480

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000134 AC: 195 AN: 1459590 Hom.: 1 Cov.: 97 AF XY: 0.000197 AC XY: 143 AN XY: 726076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.0000940 AC XY: 7 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000199 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 29, 2023

BP4 -

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 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.058	T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0098	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.73	N;.;.
REVEL	Benign	0.038
Sift	Uncertain	0.029	D;.;.
Sift4G	Benign	0.36	T;.;.
Polyphen		0.0090	B;.;.
Vest4		0.063
MutPred		0.12		Loss of glycosylation at P420 (P = 0.0131);.;.;
MVP		0.56
MPC		0.0046
ClinPred		0.016	T
GERP RS		1.9
Varity_R		0.062
gMVP		0.074

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: rs373261147; hg19: chr4-3494975;