chr10-92848630-C-T

Variant names:

• chr10-92848630-C-T
• rs1847160686
• NM_019053.6:c.97C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019053.6(EXOC6):​c.97C>T​(p.Leu33Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000786 in 1,272,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: EXOC6 NM_019053.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32502145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC6	NM_019053.6	c.97C>T	p.Leu33Phe	missense_variant	Exon 1 of 22	ENST00000260762.10	NP_061926.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC6	ENST00000260762.10	c.97C>T	p.Leu33Phe	missense_variant	Exon 1 of 22	1	NM_019053.6	ENSP00000260762.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.86e-7 AC: 1 AN: 1272346 Hom.: 0 Cov.: 33 AF XY: 0.00000158 AC XY: 1 AN XY: 631680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.98e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97C>T (p.L33F) alteration is located in exon 1 (coding exon 1) of the EXOC6 gene. This alteration results from a C to T substitution at nucleotide position 97, causing the leucine (L) at amino acid position 33 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.10	.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.045
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.92	D;T;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.090	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.67	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.62	P;.;B
Vest4		0.50
MutPred		0.54		Gain of phosphorylation at T32 (P = 0.1998);Gain of phosphorylation at T32 (P = 0.1998);Gain of phosphorylation at T32 (P = 0.1998);
MVP		0.45
MPC		0.28
ClinPred		0.71	D
GERP RS		2.9
Varity_R		0.12
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs1847160686; hg19: chr10-94608387;