19-11222783-CAG-C

Variant names:

• chr19-11222783-CAG-C
• rs747575528
• NM_020812.4:c.3190_3191delCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020812.4(DOCK6):​c.3190_3191delCT​(p.Leu1064ValfsTer60) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,584,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: DOCK6 NM_020812.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 19-11222783-CAG-C is Pathogenic according to our data. Variant chr19-11222783-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1206321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11222783-CAG-C is described in Lovd as [Likely_pathogenic]. Variant chr19-11222783-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK6	NM_020812.4	c.3190_3191delCT	p.Leu1064ValfsTer60	frameshift_variant	Exon 26 of 48	ENST00000294618.12	NP_065863.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK6	ENST00000294618.12	c.3190_3191delCT	p.Leu1064ValfsTer60	frameshift_variant	Exon 26 of 48	1	NM_020812.4	ENSP00000294618.6
DOCK6	ENST00000587656.6	c.3295_3296delCT	p.Leu1099ValfsTer60	frameshift_variant	Exon 27 of 49	5		ENSP00000468638.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151996 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000750 AC: 15 AN: 200066 Hom.: 0 AF XY: 0.0000653 AC XY: 7 AN XY: 107226

Gnomad AFR exome AF: 0.000171

Gnomad AMR exome AF: 0.0000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000269

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000790

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.0000670 AC: 96 AN: 1431994 Hom.: 0 AF XY: 0.0000846 AC XY: 60 AN XY: 709170

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.0000770

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.000104

Gnomad4 SAS exome AF: 0.0000852

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000638

Gnomad4 OTH exome AF: 0.0000841

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74358

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000121

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, Liu2022[paper], 25091416, 31654484, 33655927) -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu1064Valfs*60) in the DOCK6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DOCK6 are known to be pathogenic (PMID: 21820096, 25824905). This variant is present in population databases (rs747575528, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Adams-Oliver syndrome (PMID: 25091416). ClinVar contains an entry for this variant (Variation ID: 1206321). For these reasons, this variant has been classified as Pathogenic. -

Adams-Oliver syndrome 2 Pathogenic:2

Jul 30, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001206321 / PMID: 25091416). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

DOCK6-related disorder Pathogenic:1

Dec 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DOCK6 c.3190_3191delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu1064Valfs*60). This variant was reported in the homozygous and compound heterozygous states in two unrelated patients with Adams-Oliver syndrome (Lehman et al. 2014. PubMed ID: 25091416; Dudoignon et al. 2019. PubMed ID: 31654484). This variant is reported in 0.024% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in DOCK6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs747575528; hg19: chr19-11333459;