NM_015189.3:c.2429A>G

Variant names:

• chr2-72179342-T-C
• rs188707447
• NM_015189.3:c.2429A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015189.3(EXOC6B):​c.2429A>G​(p.His810Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,607,554 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H810Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: EXOC6B NM_015189.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.39
• Publications: 4 publications found

Genes affected

EXOC6B (HGNC:17085): (exocyst complex component 6B) This gene encodes a protein which is a part of the evolutionarily conserved exocyst, a multimeric protein complex necessary for exocytosis, which in turn, is crucial for cell growth, polarity and migration. Disruption of this gene may be associated with phenotypes exhibiting multiple symptoms including intellectual disability and developmental delay (DD). [provided by RefSeq, Jun 2016]

EXOC6B Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia with joint laxity, type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• spondyloepimetaphyseal dysplasia with joint laxity

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067148507).
• BP6: Variant 2-72179342-T-C is Benign according to our data. Variant chr2-72179342-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 774830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00189 (287/152044) while in subpopulation NFE AF = 0.0029 (197/67964). AF 95% confidence interval is 0.00257. There are 0 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015189.3. 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
	EXOC6B	NM_015189.3	MANE Select	c.2429A>G	p.His810Arg	missense	Exon 22 of 22	NP_056004.1	Q9Y2D4-1
	EXOC6B	NM_001321729.2		c.2441A>G	p.His814Arg	missense	Exon 23 of 23	NP_001308658.1	A0A0U1RRB6
	EXOC6B	NM_001321730.2		c.2306A>G	p.His769Arg	missense	Exon 22 of 22	NP_001308659.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC6B	ENST00000272427.11	TSL:1 MANE Select	c.2429A>G	p.His810Arg	missense	Exon 22 of 22	ENSP00000272427.7	Q9Y2D4-1
	EXOC6B	ENST00000971151.1		c.2513A>G	p.His838Arg	missense	Exon 24 of 24	ENSP00000641210.1
	EXOC6B	ENST00000971153.1		c.2474A>G	p.His825Arg	missense	Exon 23 of 23	ENSP00000641212.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00193 AC: 465 AN: 240808 AF XY: 0.00196

Gnomad AFR exome AF: 0.000208

Gnomad AMR exome AF: 0.000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00678

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.00246 AC: 3576 AN: 1455510 Hom.: 6 Cov.: 31 AF XY: 0.00239 AC XY: 1729 AN XY: 723472

African (AFR) AF: 0.000299 AC: 10 AN: 33400

American (AMR) AF: 0.000972 AC: 43 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85208

European-Finnish (FIN) AF: 0.00603 AC: 319 AN: 52908

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5580

European-Non Finnish (NFE) AF: 0.00279 AC: 3088 AN: 1108736

Other (OTH) AF: 0.00188 AC: 113 AN: 60094

GnomAD4 genome AF: 0.00189 AC: 287 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74326

African (AFR) AF: 0.000337 AC: 14 AN: 41482

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.00624 AC: 66 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00138

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000717 AC: 3

ESP6500EA AF: 0.00249 AC: 21

ExAC AF: 0.00192 AC: 232

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EXOC6B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.051
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		0.24	B
Vest4		0.34
MVP		0.31
MPC		0.97
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.39
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs188707447; hg19: chr2-72406471;