19-11222821-C-A

Variant names:

• chr19-11222821-C-A
• rs774877657
• NM_020812.4:c.3154G>T

Variant summary

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

The NM_020812.4(DOCK6):​c.3154G>T​(p.Glu1052*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DOCK6 NM_020812.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

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]

DOCK6 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Adams-Oliver syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020812.4. 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
	DOCK6	NM_020812.4	MANE Select	c.3154G>T	p.Glu1052*	stop_gained	Exon 26 of 48	NP_065863.2	Q96HP0
	DOCK6	NM_001367830.1		c.3259G>T	p.Glu1087*	stop_gained	Exon 27 of 49	NP_001354759.1	K7ESB7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK6	ENST00000294618.12	TSL:1 MANE Select	c.3154G>T	p.Glu1052*	stop_gained	Exon 26 of 48	ENSP00000294618.6	Q96HP0
	DOCK6	ENST00000587656.6	TSL:5	c.3259G>T	p.Glu1087*	stop_gained	Exon 27 of 49	ENSP00000468638.2	K7ESB7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443964 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 716400

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000301 AC: 1 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 41174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 38966

South Asian (SAS) AF: 0.00 AC: 0 AN: 83584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103794

Other (OTH) AF: 0.00 AC: 0 AN: 59848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
Vest4		0.93
GERP RS		4.8
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs774877657; hg19: chr19-11333497; COSMIC: COSV99626650; COSMIC: COSV99626650;