10-92935860-C-T

Position:

• chr10-92935860-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019053.6(EXOC6):​c.1187C>T​(p.Thr396Ile) variant causes a missense change. The variant allele was found at a frequency of 0.717 in 1,601,914 control chromosomes in the GnomAD database, including 418,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.78 (47978 hom., cov: 32)
  • Exomes 𝑓: 0.71 (370645 hom.)
• Consequence: EXOC6 NM_019053.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.29

Genes affected

EXOC6 (HGNC:23196): (exocyst complex component 6) The protein encoded by this gene is highly similar to the Saccharomyces cerevisiae SEC15 gene product, which is essential for vesicular traffic from the Golgi apparatus to the cell surface in yeast. It is one of the components of a multiprotein complex required for exocytosis. The 5' portion of this gene and two neighboring cytochrome p450 genes are included in a deletion that results in an autosomal-dominant form of nonsyndromic optic nerve aplasia (ONA). Alternative splicing and the use of alternative promoters results in multiple transcript variants. A paralogous gene encoding a similar protein is present on chromosome 2. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.461329E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOC6	NM_019053.6	c.1187C>T	p.Thr396Ile	missense_variant	12/22	ENST00000260762.10	NP_061926.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOC6	ENST00000260762.10	c.1187C>T	p.Thr396Ile	missense_variant	12/22	1	NM_019053.6	ENSP00000260762.6

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119090 AN: 151994 Hom.: 47915 Cov.: 32

Gnomad AFR AF: 0.943

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.791

GnomAD3 exomes AF: 0.770 AC: 191175 AN: 248206 Hom.: 75292 AF XY: 0.765 AC XY: 102677 AN XY: 134300

Gnomad AFR exome AF: 0.948

Gnomad AMR exome AF: 0.876

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.997

Gnomad SAS exome AF: 0.839

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.689

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.710 AC: 1028888 AN: 1449802 Hom.: 370645 Cov.: 31 AF XY: 0.712 AC XY: 514203 AN XY: 721940

Gnomad4 AFR exome AF: 0.952

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.734

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.837

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.677

Gnomad4 OTH exome AF: 0.734

GnomAD4 genome AF: 0.784 AC: 119209 AN: 152112 Hom.: 47978 Cov.: 32 AF XY: 0.785 AC XY: 58335 AN XY: 74342

Gnomad4 AFR AF: 0.943

Gnomad4 AMR AF: 0.832

Gnomad4 ASJ AF: 0.745

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.842

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.793

Alfa AF: 0.712 Hom.: 90100

Bravo AF: 0.805

TwinsUK AF: 0.675 AC: 2504

ALSPAC AF: 0.677 AC: 2608

ESP6500AA AF: 0.936 AC: 4124

ESP6500EA AF: 0.689 AC: 5925

ExAC AF: 0.772 AC: 93762

Asia WGS AF: 0.936 AC: 3253 AN: 3476

EpiCase AF: 0.688

EpiControl AF: 0.693

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.15
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	5.5e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.1	.;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	4.1	N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.12
MPC		0.24
ClinPred		0.018	T
GERP RS		5.8
Varity_R		0.078
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1326331; hg19: chr10-94695617; COSMIC: COSV53333557;