chr10-92915765-A-G

Position:

• chr10-92915765-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019053.6(EXOC6):​c.671A>G​(p.His224Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 1,372,428 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: EXOC6 NM_019053.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

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]

EXOC6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17412058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOC6	NM_019053.6	c.671A>G	p.His224Arg	missense_variant	7/22	ENST00000260762.10	NP_061926.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOC6	ENST00000260762.10	c.671A>G	p.His224Arg	missense_variant	7/22	1	NM_019053.6	ENSP00000260762.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1372428 Hom.: 0 Cov.: 28 AF XY: 0.00000294 AC XY: 2 AN XY: 680714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000423

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.671A>G (p.H224R) alteration is located in exon 7 (coding exon 7) of the EXOC6 gene. This alteration results from a A to G substitution at nucleotide position 671, causing the histidine (H) at amino acid position 224 to be replaced by an arginine (R). 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	Benign	0.067
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.095
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;.;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.076
Sift	Benign	0.056	T;D;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0010, 0.0	.;B;B
Vest4		0.23
MVP		0.33
MPC		0.28
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-94675522;