rs61748993

Variant names:

• chrX-153905157-G-A
• rs61748993
• NM_000054.7:c.12G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000054.7(AVPR2):​c.12G>A​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,210,577 control chromosomes in the GnomAD database, including 5 homozygotes. There are 260 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., 108 hem., cov: 24)
  • Exomes 𝑓: 0.00047 (3 hom. 152 hem.)
• Consequence: AVPR2 NM_000054.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.76
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-153905157-G-A is Benign according to our data. Variant chrX-153905157-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00413 (465/112543) while in subpopulation AFR AF = 0.0147 (456/31023). AF 95% confidence interval is 0.0136. There are 2 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 465 XL,AD gene.

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.12G>A	p.Ala4Ala	synonymous	Exon 2 of 4	NP_000045.1	P30518-1
	AVPR2	NM_001146151.3		c.12G>A	p.Ala4Ala	synonymous	Exon 2 of 3	NP_001139623.1	P30518-2
	AVPR2	NR_027419.2		n.452G>A		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVPR2	ENST00000646375.2	MANE Select	c.12G>A	p.Ala4Ala	synonymous	Exon 2 of 4	ENSP00000496396.1	P30518-1
	AVPR2	ENST00000337474.5	TSL:1	c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 3	ENSP00000338072.5	P30518-1
	AVPR2	ENST00000370049.1	TSL:1	c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 2	ENSP00000359066.1	P30518-2

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 462 AN: 112488 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000372

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.00116 AC: 213 AN: 183130 AF XY: 0.000783

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000474 AC: 520 AN: 1098034 Hom.: 3 Cov.: 32 AF XY: 0.000418 AC XY: 152 AN XY: 363464

African (AFR) AF: 0.0160 AC: 422 AN: 26395

American (AMR) AF: 0.000653 AC: 23 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00219 AC: 9 AN: 4101

European-Non Finnish (NFE) AF: 0.0000297 AC: 25 AN: 842014

Other (OTH) AF: 0.000825 AC: 38 AN: 46074

GnomAD4 genome AF: 0.00413 AC: 465 AN: 112543 Hom.: 2 Cov.: 24 AF XY: 0.00311 AC XY: 108 AN XY: 34713

African (AFR) AF: 0.0147 AC: 456 AN: 31023

American (AMR) AF: 0.000371 AC: 4 AN: 10769

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53160

Other (OTH) AF: 0.00262 AC: 4 AN: 1526

Alfa AF: 0.00126 Hom.: 4

Bravo AF: 0.00460

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Diabetes insipidus, nephrogenic, X-linked (1)
-	-	1	Diabetes insipidus, nephrogenic, X-linked;C1845202:Nephrogenic syndrome of inappropriate antidiuresis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.54
PhyloP100		-1.8
PromoterAI		-0.064	Neutral
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: rs61748993; hg19: chrX-153170611;