rs565984758

Variant names:

• chr14-57209749-G-C
• rs565984758
• NM_006544.4:c.1756C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006544.4(EXOC5):​c.1756C>G​(p.Gln586Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,611,562 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81
• Publications: 0 publications found

Genes affected

EXOC5 (HGNC:10696): (exocyst complex component 5) The protein encoded by this gene is a component of the exocyst complex, a multiple protein complex essential for targeting exocytic vesicles to specific docking sites on the plasma membrane. Though best characterized in yeast, the component proteins and functions of exocyst complex have been demonstrated to be highly conserved in higher eukaryotes. At least eight components of the exocyst complex, including this protein, are found to interact with the actin cytoskeletal remodeling and vesicle transport machinery. The complex is also essential for the biogenesis of epithelial cell surface polarity. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006544.4. 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
	EXOC5	NM_006544.4	MANE Select	c.1756C>G	p.Gln586Glu	missense	Exon 17 of 18	NP_006535.1	O00471

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC5	ENST00000621441.5	TSL:1 MANE Select	c.1756C>G	p.Gln586Glu	missense	Exon 17 of 18	ENSP00000484855.1	O00471
	EXOC5	ENST00000554011.5	TSL:1	n.1475C>G		non_coding_transcript_exon	Exon 7 of 8
	EXOC5	ENST00000854286.1		c.1870C>G	p.Gln624Glu	missense	Exon 17 of 18	ENSP00000524345.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244776 AF XY: 0.00000754

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459438 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725782

African (AFR) AF: 0.000120 AC: 4 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110710

Other (OTH) AF: 0.0000166 AC: 1 AN: 60266

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000120 AC: 5 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000653707), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0093	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.77	T
Polyphen		0.049	B
Vest4		0.80
MutPred		0.68		Loss of MoRF binding (P = 0.028)
MVP		0.89
MPC		0.64
ClinPred		0.26	T
GERP RS		5.2
Varity_R		0.23
gMVP		0.58
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs565984758; hg19: chr14-57676467;