Genetic Variant EXOC6B:c.1801-2A>C (chr2-72465341-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_015189.3(EXOC6B):c.1801-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

EXOC6B
NM_015189.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

Genes affected

EXOC6B (HGNC:17085): (exocyst complex component 6B) This gene encodes a protein which is a part of the evolutionarily conserved exocyst, a multimeric protein complex necessary for exocytosis, which in turn, is crucial for cell growth, polarity and migration. Disruption of this gene may be associated with phenotypes exhibiting multiple symptoms including intellectual disability and developmental delay (DD). [provided by RefSeq, Jun 2016]

EXOC6B Gene-Disease associations (from GenCC):

spondyloepimetaphyseal dysplasia with joint laxity, type 3
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
spondyloepimetaphyseal dysplasia with joint laxity
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EXOC6B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.073891625 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC6B	NM_015189.3 link	c.1801-2A>C		splice_acceptor_variant, intron_variant	Intron 17 of 21	ENST00000272427.11	NP_056004.1	Q9Y2D4-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXOC6B	ENST00000272427.11 link	c.1801-2A>C	splice_acceptor_variant, intron_variant	Intron 17 of 21	1	NM_015189.3	ENSP00000272427.7	Q9Y2D4-1
EXOC6B	ENST00000410104.1 link	c.1801-2A>C	splice_acceptor_variant, intron_variant	Intron 17 of 17	1		ENSP00000386698.1	J3QT38
EXOC6B	ENST00000634650.1 link	c.1801-2A>C	splice_acceptor_variant, intron_variant	Intron 17 of 22	5		ENSP00000489442.1	A0A0U1RRB6
EXOC6B	ENST00000464347.2 link	n.223-2A>C	splice_acceptor_variant, intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412646

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31758

American (AMR)

AF:

0.00

AC:

AN:

35458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24634

East Asian (EAS)

AF:

0.00

AC:

AN:

38092

South Asian (SAS)

AF:

0.00

AC:

AN:

79244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088130

Other (OTH)

AF:

0.0000171

AC:

AN:

58404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

PhyloP100

8.0

GERP RS

3.9

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.95

Position offset: -10

DS_AL_spliceai

1.0

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over