Genetic Variant EXOC6:p.Leu8Pro (chr10-92848556-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_019053.6(EXOC6):c.23T>C(p.Leu8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,431,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L8V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

EXOC6
NM_019053.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Publications

0 publications found

Variant links:

Genes affected

EXOC6 (HGNC:23196): (exocyst complex component 6) The protein encoded by this gene is highly similar to the Saccharomyces cerevisiae SEC15 gene product, which is essential for vesicular traffic from the Golgi apparatus to the cell surface in yeast. It is one of the components of a multiprotein complex required for exocytosis. The 5' portion of this gene and two neighboring cytochrome p450 genes are included in a deletion that results in an autosomal-dominant form of nonsyndromic optic nerve aplasia (ONA). Alternative splicing and the use of alternative promoters results in multiple transcript variants. A paralogous gene encoding a similar protein is present on chromosome 2. [provided by RefSeq, Jan 2016]

EXOC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15692267).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019053.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOC6	NM_019053.6	MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 1 of 22	NP_061926.3
EXOC6	NM_001319195.2		c.23T>C	p.Leu8Pro	missense	Exon 1 of 22	NP_001306124.1
EXOC6	NM_001319200.2		c.23T>C	p.Leu8Pro	missense	Exon 1 of 18	NP_001306129.1	E7EW84

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOC6	ENST00000260762.10	TSL:1 MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 1 of 22	ENSP00000260762.6	Q8TAG9-1
EXOC6	ENST00000443748.6	TSL:1	c.23T>C	p.Leu8Pro	missense	Exon 1 of 18	ENSP00000396206.2	E7EW84
EXOC6	ENST00000371543.5	TSL:2	c.23T>C	p.Leu8Pro	missense	Exon 1 of 5	ENSP00000360598.1	B1AP46

Frequencies

GnomAD3 genomes

AF:

0.000113

AC:

AN:

150200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000413

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000220

AC:

AN:

181816

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000242

Gnomad AMR exome

AF:

0.0000380

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000624

AC:

AN:

1281464

Hom.:

Cov.:

AF XY:

0.00000314

AC XY:

AN XY:

637046

show subpopulations

African (AFR)

AF:

0.000237

AC:

AN:

25308

American (AMR)

AF:

0.0000298

AC:

AN:

33572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19864

East Asian (EAS)

AF:

0.00

AC:

AN:

22962

South Asian (SAS)

AF:

0.00

AC:

AN:

76256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4974

European-Non Finnish (NFE)

AF:

9.94e-7

AC:

AN:

1005930

Other (OTH)

AF:

0.00

AC:

AN:

49140

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

Age Distribution

Exome Het

Variant carriers

<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:

0.000113

AC:

AN:

150200

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

AN XY:

73294

show subpopulations

African (AFR)

AF:

0.000413

AC:

AN:

41190

American (AMR)

AF:

0.00

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67310

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000132

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000415

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

PhyloP100

2.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.76

REVEL

Benign

0.037

Sift

Benign

0.047

Sift4G

Benign

0.065

Polyphen

0.35

Vest4

0.24

MVP

0.45

MPC

0.52

ClinPred

0.086

GERP RS

1.5

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.35

Mutation Taster

=67/33

polymorphism

(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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over