rs1553847993

Variant names:

• chr4-3485618-CCCCACCAAGGGCC-GGACGGTTCTA
• rs1553847993
• NM_173660.5:c.612_625delCCCCACCAAGGGCCinsGGACGGTTCTA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001164673.2(DOK7):​c.601_614delCCCCACCAAGGGCCinsGGACGGTTCTA​(p.Pro201_Pro205delinsGlyArgPheTyr) variant causes a stop gained, disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P201P) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DOK7 NM_001164673.2 stop_gained, disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.66
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3485618-CCCCACCAAGGGCC-GGACGGTTCTA is Pathogenic according to our data. Variant chr4-3485618-CCCCACCAAGGGCC-GGACGGTTCTA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434961.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164673.2. 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.612_625delCCCCACCAAGGGCCinsGGACGGTTCTA	p.Pro205_Pro209delinsAspGlySerThr	missense disruptive_inframe_deletion	N/A	NP_775931.3
	DOK7	NM_001164673.2		c.601_614delCCCCACCAAGGGCCinsGGACGGTTCTA	p.Pro201_Pro205delinsGlyArgPheTyr	stop_gained disruptive_inframe_deletion	N/A	NP_001158145.1
	DOK7	NM_001301071.2		c.612_625delCCCCACCAAGGGCCinsGGACGGTTCTA	p.Pro205_Pro209delinsAspGlySerThr	missense disruptive_inframe_deletion	N/A	NP_001288000.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.612_625delCCCCACCAAGGGCCinsGGACGGTTCTA	p.Pro205_Pro209delinsAspGlySerThr	missense disruptive_inframe_deletion	N/A	ENSP00000344432.5
	DOK7	ENST00000513995.1	TSL:1	n.270_283delCCCCACCAAGGGCCinsGGACGGTTCTA		non_coding_transcript_exon	Exon 1 of 3
	DOK7	ENST00000507039.5	TSL:2	c.601_614delCCCCACCAAGGGCCinsGGACGGTTCTA	p.Pro201_Pro205delinsGlyArgPheTyr	stop_gained disruptive_inframe_deletion	N/A	ENSP00000423614.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553847993; hg19: chr4-3487345;