NM_175876.5:c.2015C>G

Variant names:

• chr1-231335731-G-C
• rs116427277
• NM_175876.5:c.2015C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_175876.5(EXOC8):​c.2015C>G​(p.Ala672Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,614,116 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (32 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (17 hom.)
• Consequence: EXOC8 NM_175876.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.71
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006480545).
• BP6: Variant 1-231335731-G-C is Benign according to our data. Variant chr1-231335731-G-C is described in ClinVar as Benign. ClinVar VariationId is 767762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00978 (1489/152234) while in subpopulation AFR AF = 0.0348 (1443/41522). AF 95% confidence interval is 0.0333. There are 32 homozygotes in GnomAd4. There are 678 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

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.2015C>G	p.Ala672Gly	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.2015C>G	p.Ala672Gly	missense	Exon 1 of 1	ENSP00000355605.2	Q8IYI6

Frequencies

GnomAD3 genomes AF: 0.00977 AC: 1486 AN: 152116 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.0000735

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00266 AC: 668 AN: 251426 AF XY: 0.00185

Gnomad AFR exome AF: 0.0373

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000984 AC: 1438 AN: 1461882 Hom.: 17 Cov.: 32 AF XY: 0.000820 AC XY: 596 AN XY: 727242

African (AFR) AF: 0.0368 AC: 1231 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112008

Other (OTH) AF: 0.00156 AC: 94 AN: 60396

GnomAD4 genome AF: 0.00978 AC: 1489 AN: 152234 Hom.: 32 Cov.: 32 AF XY: 0.00911 AC XY: 678 AN XY: 74440

African (AFR) AF: 0.0348 AC: 1443 AN: 41522

American (AMR) AF: 0.00196 AC: 30 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.0115

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00332 AC: 403

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.7
PrimateAI	Uncertain	0.59	T
REVEL	Benign	0.27
Sift4G	Benign	0.33	T
Polyphen		0.084	B
Vest4		0.36
MVP		0.34
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.14
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs116427277; hg19: chr1-231471477; COSMIC: COSV99039041; COSMIC: COSV99039041;