2-72263190-G-T

Variant names:

• chr2-72263190-G-T
• rs6546753
• NM_015189.3:c.2196+71757C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015189.3(EXOC6B):​c.2196+71757C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 152,026 control chromosomes in the GnomAD database, including 21,019 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (21018 hom., cov: 32)
  • Exomes 𝑓: 0.36 (1 hom.)
• Consequence: EXOC6B NM_015189.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.591
• Publications: 9 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: STRONG Submitted by: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC6B	NM_015189.3	MANE Select	c.2196+71757C>A		intron	N/A	NP_056004.1
	EXOC6B	NM_001321729.2		c.2196+71757C>A		intron	N/A	NP_001308658.1
	EXOC6B	NM_001321731.2		c.2196+71757C>A		intron	N/A	NP_001308660.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC6B	ENST00000272427.11	TSL:1 MANE Select	c.2196+71757C>A		intron	N/A	ENSP00000272427.7
	EXOC6B	ENST00000634650.1	TSL:5	c.2196+71757C>A		intron	N/A	ENSP00000489442.1
	EXOC6B	ENST00000471335.5	TSL:4	n.117+71757C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69525 AN: 151894 Hom.: 20958 Cov.: 32

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.403

GnomAD4 exome AF: 0.357 AC: 5 AN: 14 Hom.: 1 AF XY: 0.500 AC XY: 5 AN XY: 10

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

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 3 AN: 12

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.458 AC: 69649 AN: 152012 Hom.: 21018 Cov.: 32 AF XY: 0.447 AC XY: 33199 AN XY: 74296

African (AFR) AF: 0.861 AC: 35705 AN: 41470

American (AMR) AF: 0.360 AC: 5487 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 827 AN: 3468

East Asian (EAS) AF: 0.0285 AC: 147 AN: 5166

South Asian (SAS) AF: 0.127 AC: 611 AN: 4818

European-Finnish (FIN) AF: 0.331 AC: 3499 AN: 10556

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22225 AN: 67970

Other (OTH) AF: 0.405 AC: 856 AN: 2114

Alfa AF: 0.384 Hom.: 2298

Bravo AF: 0.481

Asia WGS AF: 0.143 AC: 500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.72
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs6546753; hg19: chr2-72490319;