Variant chr1-231335927-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_175876.5(EXOC8):c.1819G>C(p.Asp607His) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,614,190 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 7 hom. )

Consequence

EXOC8
NM_175876.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.98

Variant links:

Genes affected

EXOC8 (HGNC:24659): (exocyst complex component 8) This gene encodes a component of the exocyst complex, an evolutionarily conserved multi-protein complex that plays a critical role in vesicular trafficking and the secretory pathway by targeting post-Golgi vesicles to the plasma membrane. This protein is a target of activated Ral subfamily of GTPases and thereby regulates exocytosis by tethering vesicles to the plasma membrane. Mutations in this gene may be related to Joubert syndrome. [provided by RefSeq, Sep 2016]

EXOC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031941026).

BS2

High Homozygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC8	NM_175876.5 linkuse as main transcript	c.1819G>C	p.Asp607His	missense_variant	1/1	ENST00000366645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC8	ENST00000366645.1 linkuse as main transcript	c.1819G>C	p.Asp607His	missense_variant	1/1		NM_175876.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000861

AC:

131

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000696

AC:

175

AN:

251394

Hom.:

AF XY:

0.000685

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00183

AC:

2676

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1246

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00231

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152322

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.000941

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 607 of the EXOC8 protein (p.Asp607His). This variant is present in population databases (rs75215445, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EXOC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1361829). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Benign

0.033

MetaRNN

Benign

0.032

MetaSVM

Uncertain

-0.0019

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

REVEL

Uncertain

0.47

Sift4G

Uncertain

0.0040

Polyphen

0.92

Vest4

0.20

MVP

0.44

ClinPred

0.19

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over