1-231336394-G-T

Variant names:

• chr1-231336394-G-T
• rs140965565
• NM_175876.5:c.1352C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_175876.5(EXOC8):​c.1352C>A​(p.Ala451Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A451V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOC8 NM_175876.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

EXOC8 (HGNC:24659): (exocyst complex component 8) This gene encodes a component of the exocyst complex, an evolutionarily conserved multi-protein complex that plays a critical role in vesicular trafficking and the secretory pathway by targeting post-Golgi vesicles to the plasma membrane. This protein is a target of activated Ral subfamily of GTPases and thereby regulates exocytosis by tethering vesicles to the plasma membrane. Mutations in this gene may be related to Joubert syndrome. [provided by RefSeq, Sep 2016]

EXOC8 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, seizures, and brain atrophy

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175876.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC8	NM_175876.5	MANE Select	c.1352C>A	p.Ala451Asp	missense	Exon 1 of 1	NP_787072.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC8	ENST00000366645.1	TSL:6 MANE Select	c.1352C>A	p.Ala451Asp	missense	Exon 1 of 1	ENSP00000355605.2	Q8IYI6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
REVEL	Uncertain	0.46
Sift4G	Uncertain	0.0050	D
Polyphen		0.91	P
Vest4		0.70
MutPred		0.70		Loss of MoRF binding (P = 0.2152)
MVP		0.47
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.58
gMVP		0.63
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs140965565; hg19: chr1-231472140;