rs1037224921

Variant names:

• chr4-3493040-C-G
• rs1037224921
• NM_173660.5:c.1054C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-3493040-C-G
• chr4-3493040-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173660.5(DOK7):​c.1054C>G​(p.Leu352Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L352L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• Publications: 0 publications found

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]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12748381).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.1054C>G	p.Leu352Val	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1054C>G	p.Leu352Val	missense	Exon 7 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.622C>G	p.Leu208Val	missense	Exon 5 of 8	NP_001350740.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1054C>G	p.Leu352Val	missense	Exon 7 of 7	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.622C>G	p.Leu208Val	missense	Exon 5 of 8	ENSP00000495701.1
	DOK7	ENST00000515886.5	TSL:2	c.124C>G	p.Leu42Val	missense	Exon 4 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420670 Hom.: 0 Cov.: 111 AF XY: 0.00 AC XY: 0 AN XY: 704386

African (AFR) AF: 0.00 AC: 0 AN: 32944

American (AMR) AF: 0.00 AC: 0 AN: 39892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25532

East Asian (EAS) AF: 0.00 AC: 0 AN: 38124

South Asian (SAS) AF: 0.00 AC: 0 AN: 82312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096188

Other (OTH) AF: 0.00 AC: 0 AN: 59082

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.081
Sift	Uncertain	0.022	D
Sift4G	Benign	0.15	T
Polyphen		0.020	B
Vest4		0.12
MutPred		0.23		Gain of catalytic residue at L352 (P = 0.0123)
MVP		0.53
MPC		0.0045
ClinPred		0.32	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.17
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1037224921; hg19: chr4-3494767;