rs879255538

Variant names:

• chrX-18994919-CA-C
• rs879255538
• NM_001079858.3:c.2845delT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001079858.3(ADGRG2):​c.2845delT​(p.Cys949AlafsTer81) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ADGRG2 NM_001079858.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.50
• Publications: 2 publications found

Genes affected

ADGRG2 (HGNC:4516): (adhesion G protein-coupled receptor G2) This gene encodes a member of the G protein-coupled receptor family described as an epididymis-specific transmembrane protein. The encoded protein may be proteolytically processed as it contains a motif shown to be a protein scission motif in some members of this family (PMID: 11973329). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ADGRG2 Gene-Disease associations (from GenCC):

• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286724 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0684 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18994919-CA-C is Pathogenic according to our data. Variant chrX-18994919-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 253013.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079858.3. 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
	ADGRG2	NM_001079858.3	MANE Select	c.2845delT	p.Cys949AlafsTer81	frameshift	Exon 28 of 29	NP_001073327.1	Q8IZP9-1
	ADGRG2	NM_005756.4		c.2836delT	p.Cys946AlafsTer81	frameshift	Exon 28 of 29	NP_005747.2	Q8IZP9-2
	ADGRG2	NM_001079859.3		c.2803delT	p.Cys935AlafsTer81	frameshift	Exon 27 of 28	NP_001073328.1	Q8IZP9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG2	ENST00000379869.8	TSL:1 MANE Select	c.2845delT	p.Cys949AlafsTer81	frameshift	Exon 28 of 29	ENSP00000369198.3	Q8IZP9-1
	ADGRG2	ENST00000357991.7	TSL:1	c.2836delT	p.Cys946AlafsTer81	frameshift	Exon 28 of 29	ENSP00000350680.3	Q8IZP9-2
	ADGRG2	ENST00000356606.8	TSL:1	c.2803delT	p.Cys935AlafsTer81	frameshift	Exon 27 of 28	ENSP00000349015.4	Q8IZP9-4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Vas deferens, congenital bilateral aplasia of, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs879255538;

hg19: chrX-19013037;