rs506121

Variant names:

• chr9-271638-C-A
• rs506121
• NM_203447.4:c.65C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-271638-C-A
• chr9-271638-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203447.4(DOCK8):​c.65C>A​(p.Ala22Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 28 publications found

Genes affected

DOCK8 (HGNC:19191): (dedicator of cytokinesis 8) This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]

DOCK8 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000235880 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24732155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.65C>A	p.Ala22Glu	missense_variant	Exon 2 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.65C>A	p.Ala22Glu	missense_variant	Exon 2 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 5680

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.000033
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.0	B
Vest4		0.31
MutPred		0.51		Gain of solvent accessibility (P = 0.0145);
MVP		0.58
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.45
gMVP		0.63
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs506121; hg19: chr9-271638;