6-497375-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_018303.6(EXOC2):c.2551G>A(p.Ala851Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EXOC2
NM_018303.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

Publications

0 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)

EXOC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC2	NM_018303.6 link	c.2551G>A	p.Ala851Thr	missense_variant	Exon 25 of 28	ENST00000230449.9	NP_060773.3	Q96KP1A0A024QZT2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC2	ENST00000230449.9 link	c.2551G>A	p.Ala851Thr	missense_variant	Exon 25 of 28	1	NM_018303.6	ENSP00000230449.4		Q96KP1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250456

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.000314

AC:

AN:

85866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111672

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2551G>A (p.A851T) alteration is located in exon 25 (coding exon 24) of the EXOC2 gene. This alteration results from a G to A substitution at nucleotide position 2551, causing the alanine (A) at amino acid position 851 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

Benign

0.21

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

0.071

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

PhyloP100

5.8

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

REVEL

Benign

0.22

Sift

Benign

0.25

Sift4G

Benign

0.39

Polyphen

0.030

Vest4

0.82

MutPred

0.77

Loss of ubiquitination at K848 (P = 0.1381);

MVP

0.52

MPC

0.19

ClinPred

0.18

GERP RS

5.2

Varity_R

0.16

gMVP

0.50

Mutation Taster

=32/68

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-497375-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over