NM_173660.5:c.-2_1delAGA

Variant names:

• chr4-3463370-CAGA-C
• rs1726066680
• NM_173660.5:c.-2_1delAGA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_173660.5(DOK7):​c.-2_1delAGA​(p.Met1del) variant causes a start lost, conservative inframe deletion change. The variant allele was found at a frequency of 0.00000224 in 1,337,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DOK7 NM_173660.5 start_lost, conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

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.-2_1delAGA	p.Met1del	start_lost conservative_inframe_deletion	Exon 1 of 7	NP_775931.3
	DOK7	NM_173660.5	MANE Select	c.-2_1delAGA		5_prime_UTR	Exon 1 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.-2_1delAGA	p.Met1del	start_lost conservative_inframe_deletion	Exon 1 of 10	NP_001288000.1	Q18PE1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.-2_1delAGA	p.Met1del	start_lost conservative_inframe_deletion	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.-2_1delAGA		5_prime_UTR	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.-2_1delAGA	p.Met1del	start_lost conservative_inframe_deletion	Exon 1 of 8	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1337576 Hom.: 0 AF XY: 0.00000151 AC XY: 1 AN XY: 662146

African (AFR) AF: 0.00 AC: 0 AN: 27188

American (AMR) AF: 0.00 AC: 0 AN: 24988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21910

East Asian (EAS) AF: 0.00 AC: 0 AN: 32648

South Asian (SAS) AF: 0.00 AC: 0 AN: 70500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3862

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1065092

Other (OTH) AF: 0.00 AC: 0 AN: 55298

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8

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: rs1726066680; hg19: chr4-3465097;