rs149668713

Variant names:

• chrX-153906246-G-A
• rs149668713
• NM_000054.7:c.740G>A
• AVPR2 p.Arg247His

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000054.7(AVPR2):​c.740G>A​(p.Arg247His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,206,443 control chromosomes in the GnomAD database, including 2 homozygotes. There are 168 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., 57 hem., cov: 25)
  • Exomes 𝑓: 0.00036 (1 hom. 111 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00900
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nephrogenic syndrome of inappropriate antidiuresis

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004691303).
• BP6: Variant X-153906246-G-A is Benign according to our data. Variant chrX-153906246-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00197 (222/112671) while in subpopulation AFR AF = 0.0068 (212/31179). AF 95% confidence interval is 0.00605. There are 1 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High AC in GnomAd4 at 222 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.740G>A	p.Arg247His	missense	Exon 3 of 4	NP_000045.1	P30518-1
	AVPR2	NM_001146151.3		c.740G>A	p.Arg247His	missense	Exon 3 of 3	NP_001139623.1	P30518-2
	AVPR2	NR_027419.2		n.693G>A		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVPR2	ENST00000646375.2	MANE Select	c.740G>A	p.Arg247His	missense	Exon 3 of 4	ENSP00000496396.1	P30518-1
	AVPR2	ENST00000337474.5	TSL:1	c.740G>A	p.Arg247His	missense	Exon 2 of 3	ENSP00000338072.5	P30518-1
	AVPR2	ENST00000370049.1	TSL:1	c.740G>A	p.Arg247His	missense	Exon 2 of 2	ENSP00000359066.1	P30518-2

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 224 AN: 112618 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000649

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000359

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000566

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000688 AC: 126 AN: 183028 AF XY: 0.000429

Gnomad AFR exome AF: 0.00829

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000356 AC: 389 AN: 1093772 Hom.: 1 Cov.: 35 AF XY: 0.000306 AC XY: 111 AN XY: 362684

African (AFR) AF: 0.00857 AC: 226 AN: 26373

American (AMR) AF: 0.000398 AC: 14 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19131

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.000153 AC: 128 AN: 838429

Other (OTH) AF: 0.000436 AC: 20 AN: 45906

GnomAD4 genome AF: 0.00197 AC: 222 AN: 112671 Hom.: 1 Cov.: 25 AF XY: 0.00162 AC XY: 57 AN XY: 35153

African (AFR) AF: 0.00680 AC: 212 AN: 31179

American (AMR) AF: 0.000649 AC: 7 AN: 10793

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2781

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6281

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

European-Non Finnish (NFE) AF: 0.0000566 AC: 3 AN: 52996

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.000644 Hom.: 8

Bravo AF: 0.00231

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.62
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.0090
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.018
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Varity_R		0.036
gMVP		0.63
Mutation Taster		=99/1	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

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

Other links and lift over

dbSNP: rs149668713;

hg19: chrX-153171700;

COSMIC: COSV61685886;

COSMIC: COSV61685886;