rs577687998

Variant names:

• chr4-3463437-C-A
• rs577687998
• NM_173660.5:c.54+8C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3463437-C-A
• chr4-3463437-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173660.5(DOK7):​c.54+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 459,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: DOK7 NM_173660.5 splice_region, intron
• Scores: Splicing: ADA: 0.003138
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.54+8C>A		splice_region_variant, intron_variant	Intron 1 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.54+8C>A		splice_region_variant, intron_variant	Intron 1 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000435 AC: 2 AN: 459582 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 236976

African (AFR) AF: 0.00 AC: 0 AN: 7408

American (AMR) AF: 0.00 AC: 0 AN: 12232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9772

East Asian (EAS) AF: 0.00 AC: 0 AN: 11586

South Asian (SAS) AF: 0.00 AC: 0 AN: 47478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1458

European-Non Finnish (NFE) AF: 0.00000604 AC: 2 AN: 330880

Other (OTH) AF: 0.00 AC: 0 AN: 20332

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		-0.12
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0031
dbscSNV1_RF	Benign	0.15
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: rs577687998; hg19: chr4-3465164;