rs1064795104

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-72498492-A-C
• chr2-72498492-A-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015189.3(EXOC6B):​c.1299T>G​(p.Tyr433*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EXOC6B NM_015189.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-72498492-A-C is Pathogenic according to our data. Variant chr2-72498492-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 421388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1299T>G	p.Tyr433*	stop_gained	Exon 13 of 22	NP_056004.1
	EXOC6B	NM_001321729.2		c.1299T>G	p.Tyr433*	stop_gained	Exon 13 of 23	NP_001308658.1
	EXOC6B	NM_001321731.2		c.1299T>G	p.Tyr433*	stop_gained	Exon 13 of 23	NP_001308660.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC6B	ENST00000272427.11	TSL:1 MANE Select	c.1299T>G	p.Tyr433*	stop_gained	Exon 13 of 22	ENSP00000272427.7
	EXOC6B	ENST00000410104.1	TSL:1	c.1299T>G	p.Tyr433*	stop_gained	Exon 13 of 18	ENSP00000386698.1
	EXOC6B	ENST00000634650.1	TSL:5	c.1299T>G	p.Tyr433*	stop_gained	Exon 13 of 23	ENSP00000489442.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.083
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.24	N
PhyloP100		-0.63
Vest4		0.61
GERP RS		-3.3
Mutation Taster		=5/195	disease causing (ClinVar)

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;