NM_018303.6:c.2431G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018303.6(EXOC2):​c.2431G>A​(p.Ala811Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

EXOC2
NM_018303.6 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.75

Publications

1 publications found
Variant links:
Genes affected
EXOC2 (HGNC:24968): (exocyst complex component 2) The protein encoded by this gene is a component of the exocyst complex, a multi-protein complex essential for the polarized targeting of exocytic vesicles to specific docking sites on the plasma membrane. Though best characterized in yeast, the component proteins and the functions of the exocyst complex have been demonstrated to be highly conserved in higher eukaryotes. At least eight components of the exocyst complex, including this protein, are found to interact with the actin cytoskeletal remodeling and vesicle transport machinery. This interaction has been shown to mediate filopodia formation in fibroblasts. This protein has been shown to interact with the Ral subfamily of GTPases and thereby mediate exocytosis by tethering vesicles to the plasma membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]
EXOC2 Gene-Disease associations (from GenCC):
  • complex neurodevelopmental disorder
    Inheritance: AR Classification: LIMITED Submitted by: ClinGen
  • neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.1611807).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EXOC2NM_018303.6 linkc.2431G>A p.Ala811Thr missense_variant Exon 24 of 28 ENST00000230449.9 NP_060773.3 Q96KP1A0A024QZT2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EXOC2ENST00000230449.9 linkc.2431G>A p.Ala811Thr missense_variant Exon 24 of 28 1 NM_018303.6 ENSP00000230449.4 Q96KP1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000235
AC:
59
AN:
251214
AF XY:
0.000184
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00417
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000979
GnomAD4 exome
AF:
0.000102
AC:
149
AN:
1461058
Hom.:
1
Cov.:
30
AF XY:
0.0000991
AC XY:
72
AN XY:
726872
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33448
American (AMR)
AF:
0.000179
AC:
8
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00410
AC:
107
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000180
AC:
20
AN:
1111348
Other (OTH)
AF:
0.000232
AC:
14
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.451
Heterozygous variant carriers
0
7
15
22
30
37
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152074
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74276
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41366
American (AMR)
AF:
0.000131
AC:
2
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00490
AC:
17
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10578
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68024
Other (OTH)
AF:
0.000478
AC:
1
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000221
Hom.:
0
Bravo
AF:
0.000200
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000198
AC:
24
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 31, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2431G>A (p.A811T) alteration is located in exon 24 (coding exon 23) of the EXOC2 gene. This alteration results from a G to A substitution at nucleotide position 2431, causing the alanine (A) at amino acid position 811 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Benign
0.0061
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.38
T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.6
M
PhyloP100
6.7
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0030
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.90
MVP
0.52
MPC
0.18
ClinPred
0.13
T
GERP RS
5.4
Varity_R
0.44
gMVP
0.65
Mutation Taster
=29/71
disease causing

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

Other links and lift over

dbSNP: rs143224673; hg19: chr6-499650; API