rs1555826472

Variant names:

• chr19-11209026-AGCTCC-A
• rs1555826472
• NM_020812.4:c.4824_4828delGGAGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020812.4(DOCK6):​c.4824_4828delGGAGC​(p.Glu1609GlyfsTer19) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1608A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK6 NM_020812.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.09

Genes affected

DOCK6 (HGNC:19189): (dedicator of cytokinesis 6) This gene encodes a member of the dedicator of cytokinesis (DOCK) family of atypical guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with small GTPases and are components of intracellular signaling networks. The encoded protein is a group C DOCK protein and plays a role in actin cytoskeletal reorganization by activating the Rho GTPases Cdc42 and Rac1. Mutations in this gene are associated with Adams-Oliver syndrome 2. [provided by RefSeq, Dec 2011]

ENSG00000267082 (HGNC:56684): (DOCK6 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 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 19-11209026-AGCTCC-A is Pathogenic according to our data. Variant chr19-11209026-AGCTCC-A is described in ClinVar as [Pathogenic]. Clinvar id is 522950.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK6	NM_020812.4	c.4824_4828delGGAGC	p.Glu1609GlyfsTer19	frameshift_variant	Exon 38 of 48	ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK6	ENST00000294618.12	c.4824_4828delGGAGC	p.Glu1609GlyfsTer19	frameshift_variant	Exon 38 of 48	1	NM_020812.4	ENSP00000294618.6
DOCK6	ENST00000587656.6	c.4929_4933delGGAGC	p.Glu1644GlyfsTer19	frameshift_variant	Exon 39 of 49	5		ENSP00000468638.2
ENSG00000267082	ENST00000588634.1	n.537+2921_537+2925delTCCGC		intron_variant	Intron 2 of 2	4
DOCK6	ENST00000588666.1	c.-88_-84delGGAGC		upstream_gene_variant		5		ENSP00000467231.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome 2 Pathogenic:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555826472; hg19: chr19-11319702;