rs56689668

Variant names:

• chrX-153905526-T-G
• rs56689668
• NM_000054.7:c.26-6T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-153905526-T-G
• chrX-153905526-T-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000054.7(AVPR2):​c.26-6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (38892 hom., 33978 hem., cov: 24)
  • Exomes 𝑓: 1.0 (360821 hom. 349485 hem.)
  • Failed GnomAD Quality Control
• Consequence: AVPR2 NM_000054.7 splice_region, intron
• Scores: Splicing: ADA: 0.01070
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0360
• Publications: 12 publications found

Genes affected

AVPR2 (HGNC:897): (arginine vasopressin receptor 2) This gene encodes the vasopressin receptor, type 2, also known as the V2 receptor, which belongs to the seven-transmembrane-domain G protein-coupled receptor (GPCR) superfamily, and couples to Gs thus stimulating adenylate cyclase. The subfamily that includes the V2 receptor, the V1a and V1b vasopressin receptors, the oxytocin receptor, and isotocin and mesotocin receptors in non-mammals, is well conserved, though several members signal via other G proteins. All bind similar cyclic nonapeptide hormones. The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these 'extrarenal receptors' are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known - its absence does not appear to be detrimental in NDI patients. The gene expression has also been described in fetal lung tissue and lung cancer associated with alternative splicing. [provided by RefSeq, Jul 2008]

AVPR2 Gene-Disease associations (from GenCC):

• diabetes insipidus, nephrogenic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nephrogenic syndrome of inappropriate antidiuresis

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• nephrogenic diabetes insipidus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-153905526-T-G is Benign according to our data. Variant chrX-153905526-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000054.7. 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
	AVPR2	NM_000054.7	MANE Select	c.26-6T>G		splice_region intron	N/A	NP_000045.1	P30518-1
	AVPR2	NM_001146151.3		c.26-6T>G		splice_region intron	N/A	NP_001139623.1	P30518-2
	AVPR2	NR_027419.2		n.465+356T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVPR2	ENST00000646375.2	MANE Select	c.26-6T>G		splice_region intron	N/A	ENSP00000496396.1	P30518-1
	AVPR2	ENST00000337474.5	TSL:1	c.26-6T>G		splice_region intron	N/A	ENSP00000338072.5	P30518-1
	AVPR2	ENST00000370049.1	TSL:1	c.26-6T>G		splice_region intron	N/A	ENSP00000359066.1	P30518-2

Frequencies

GnomAD3 genomes AF: 1.00 AC: 111732 AN: 111762 Hom.: 38897 Cov.: 24

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.992

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 0.999 AC: 130924 AN: 131006 AF XY: 0.999

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.992

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 1.00 AC: 1071431 AN: 1071907 Hom.: 360821 Cov.: 43 AF XY: 1.00 AC XY: 349485 AN XY: 349645

African (AFR) AF: 1.00 AC: 25628 AN: 25628

American (AMR) AF: 1.00 AC: 31626 AN: 31626

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 18900 AN: 18900

East Asian (EAS) AF: 0.984 AC: 28065 AN: 28521

South Asian (SAS) AF: 1.00 AC: 51515 AN: 51521

European-Finnish (FIN) AF: 1.00 AC: 37803 AN: 37803

Middle Eastern (MID) AF: 1.00 AC: 3386 AN: 3387

European-Non Finnish (NFE) AF: 1.00 AC: 829515 AN: 829517

Other (OTH) AF: 1.00 AC: 44993 AN: 45004

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 1.00 AC: 111784 AN: 111814 Hom.: 38892 Cov.: 24 AF XY: 1.00 AC XY: 33978 AN XY: 33984

African (AFR) AF: 1.00 AC: 30815 AN: 30815

American (AMR) AF: 1.00 AC: 10718 AN: 10719

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2658 AN: 2658

East Asian (EAS) AF: 0.992 AC: 3486 AN: 3514

South Asian (SAS) AF: 1.00 AC: 2681 AN: 2682

European-Finnish (FIN) AF: 1.00 AC: 6068 AN: 6068

Middle Eastern (MID) AF: 1.00 AC: 219 AN: 219

European-Non Finnish (NFE) AF: 1.00 AC: 52935 AN: 52935

Other (OTH) AF: 1.00 AC: 1527 AN: 1527

Alfa AF: 1.00 Hom.: 12656

Bravo AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Diabetes insipidus, nephrogenic, X-linked (2)
-	-	1	Nephrogenic syndrome of inappropriate antidiuresis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		-0.036
PromoterAI		-0.0028	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -18

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

Other links and lift over

dbSNP: rs56689668; hg19: chrX-153170980;