rs1064795104

Positions:

• chr2-72498492-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ACMG classification

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	Protein	UniProt
EXOC6B	NM_015189.3	c.1299T>G	p.Tyr433Ter	stop_gained	13/22	ENST00000272427.11	NP_056004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOC6B	ENST00000272427.11	c.1299T>G	p.Tyr433Ter	stop_gained	13/22	1	NM_015189.3	ENSP00000272427	P4
EXOC6B	ENST00000410104.1	c.1299T>G	p.Tyr433Ter	stop_gained	13/18	1		ENSP00000386698
EXOC6B	ENST00000634650.1	c.1299T>G	p.Tyr433Ter	stop_gained	13/23	5		ENSP00000489442	A1
EXOC6B	ENST00000410112.6	c.*1010T>G		3_prime_UTR_variant, NMD_transcript_variant	12/13	5		ENSP00000386634

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.083
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.24	N
MutationTaster	Benign	1.0	A;A
Vest4		0.61
GERP RS		-3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064795104; hg19: chr2-72725621;