rs1064795104
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015189.3(EXOC6B):c.1299T>G(p.Tyr433Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
EXOC6B
NM_015189.3 stop_gained
NM_015189.3 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -0.625
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-72498492-A-C is Pathogenic according to our data. Variant chr2-72498492-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOC6B | NM_015189.3 | c.1299T>G | p.Tyr433Ter | stop_gained | 13/22 | ENST00000272427.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOC6B | ENST00000272427.11 | c.1299T>G | p.Tyr433Ter | stop_gained | 13/22 | 1 | NM_015189.3 | P4 | |
EXOC6B | ENST00000410104.1 | c.1299T>G | p.Tyr433Ter | stop_gained | 13/18 | 1 | |||
EXOC6B | ENST00000634650.1 | c.1299T>G | p.Tyr433Ter | stop_gained | 13/23 | 5 | A1 | ||
EXOC6B | ENST00000410112.6 | c.*1010T>G | 3_prime_UTR_variant, NMD_transcript_variant | 12/13 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Jan 23, 2018 | This 7 year old male with a history of seizures, severe intellectual disability, microcephaly, osteopenia, and short stature is heterozygous for a maternally-inherited nonsense variant in EXOC6B. He also has eczema that is explained by a FLG pathogenic variant and hypospadias that was repaired as an infant. He initially presented with complex febrile seizures between 2-3 years of age that progressed to global tonicity with flexion and extension, mouth clicking, and perioral cyanosis. A brain MRI at 1 year of age showed symmetrical volume loss involving the bilateral peri-arterial white matter with compensatory enlargement and mild scalloping of both atria of the lateral ventricles compatible with periventricular leukomalacia. Asymmetrical low-lying right cerebellar tonsil was also noted. Patient's mother has not undergone an MRI or renal studies, and reportedly has scoliosis but no developmental or neurological concerns. This variant is absent from gnomAD and loss of normal protein function is predicted either through protein truncation or nonsense-mediated mRNA decay. This individual also has a heterozygous paternally-inherited missense variant of uncertain significance in AUTS2. The patient's father reportedly has no overlapping phenotype. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2018 | The Y433X variant in the EXOC6B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y433X variant was not observed in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y433X variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at