2-72498492-A-G

Variant names:

• chr2-72498492-A-G
• rs1064795104
• NM_015189.3:c.1299T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_015189.3(EXOC6B):​c.1299T>C​(p.Tyr433Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EXOC6B NM_015189.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.625
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=-0.625 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC6B	NM_015189.3	c.1299T>C	p.Tyr433Tyr	synonymous_variant	Exon 13 of 22	ENST00000272427.11	NP_056004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC6B	ENST00000272427.11	c.1299T>C	p.Tyr433Tyr	synonymous_variant	Exon 13 of 22	1	NM_015189.3	ENSP00000272427.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459706 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726060

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

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.0000224 AC: 1 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111056

Other (OTH) AF: 0.00 AC: 0 AN: 60298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.3
DANN	Benign	0.40
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064795104; hg19: chr2-72725621;