rs373864257

Positions:

• chr4-3493332-C-G
• chr4-3493332-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173660.5(DOK7):​c.1346C>G​(p.Thr449Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T449M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1439279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1346C>G	p.Thr449Arg	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1346C>G	p.Thr449Arg	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.914C>G	p.Thr305Arg	missense_variant	5/8
DOK7	ENST00000515886.5	c.416C>G	p.Thr139Arg	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*567C>G		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 95

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000848 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.1
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.022	D;.;.
Sift4G	Benign	0.50	T;.;.
Polyphen		0.20	B;.;.
Vest4		0.15
MutPred		0.17		Gain of MoRF binding (P = 0.036);.;.;
MVP		0.71
MPC		0.0048
ClinPred		0.12	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.12

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: rs373864257; hg19: chr4-3495059;