10-92935860-C-T

Variant names:

• chr10-92935860-C-T
• rs1326331
• NM_019053.6:c.1187C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T396N) has been classified as Uncertain significance.

• 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
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019053.6. 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
	EXOC6	NM_019053.6	MANE Select	c.1187C>T	p.Thr396Ile	missense	Exon 12 of 22	NP_061926.3
	EXOC6	NM_001319194.2		c.1235C>T	p.Thr412Ile	missense	Exon 13 of 23	NP_001306123.1
	EXOC6	NM_001319195.2		c.1187C>T	p.Thr396Ile	missense	Exon 12 of 22	NP_001306124.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC6	ENST00000260762.10	TSL:1 MANE Select	c.1187C>T	p.Thr396Ile	missense	Exon 12 of 22	ENSP00000260762.6	Q8TAG9-1
	EXOC6	ENST00000443748.6	TSL:1	c.904-4867C>T		intron	N/A	ENSP00000396206.2	E7EW84
	EXOC6	ENST00000371552.8	TSL:5	c.1172C>T	p.Thr391Ile	missense	Exon 12 of 22	ENSP00000360607.4	Q8TAG9-2

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

GnomAD2 exomes AF: 0.770 AC: 191175 AN: 248206 AF XY: 0.765

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 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

African (AFR) AF: 0.952 AC: 31551 AN: 33148

American (AMR) AF: 0.869 AC: 38417 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 19095 AN: 26006

East Asian (EAS) AF: 0.999 AC: 39395 AN: 39444

South Asian (SAS) AF: 0.837 AC: 71756 AN: 85716

European-Finnish (FIN) AF: 0.646 AC: 34050 AN: 52682

Middle Eastern (MID) AF: 0.766 AC: 4383 AN: 5724

European-Non Finnish (NFE) AF: 0.677 AC: 746165 AN: 1102844

Other (OTH) AF: 0.734 AC: 44076 AN: 60012

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

African (AFR) AF: 0.943 AC: 39171 AN: 41534

American (AMR) AF: 0.832 AC: 12713 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2587 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5171 AN: 5190

South Asian (SAS) AF: 0.842 AC: 4069 AN: 4830

European-Finnish (FIN) AF: 0.622 AC: 6556 AN: 10536

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46373 AN: 67952

Other (OTH) AF: 0.793 AC: 1674 AN: 2110

Alfa AF: 0.727 Hom.: 131667

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 v4.9

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
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.1	N
PhyloP100		6.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	4.1	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs1326331; hg19: chr10-94695617; COSMIC: COSV53333557;