X-153905288-A-G

Variant names:

• chrX-153905288-A-G
• rs191116415
• NM_000054.7:c.25+118A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000054.7(AVPR2):​c.25+118A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00772 in 1,064,380 control chromosomes in the GnomAD database, including 386 homozygotes. There are 2,111 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (200 hom., 1113 hem., cov: 25)
  • Exomes 𝑓: 0.0043 (186 hom. 998 hem.)
• Consequence: AVPR2 NM_000054.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.17
• Publications: 0 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), 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 (BayesDel_noAF=-0.9).
• BP6: Variant X-153905288-A-G is Benign according to our data. Variant chrX-153905288-A-G is described in ClinVar as [Benign]. Clinvar id is 1286248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.25+118A>G		intron_variant	Intron 2 of 3	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.25+118A>G		intron_variant	Intron 2 of 2		NP_001139623.1
AVPR2	NR_027419.2	n.465+118A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.25+118A>G		intron_variant	Intron 2 of 3		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3782T>C		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 4157 AN: 112310 Hom.: 200 Cov.: 25

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000732

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.0356

GnomAD4 exome AF: 0.00426 AC: 4054 AN: 952015 Hom.: 186 AF XY: 0.00370 AC XY: 998 AN XY: 269369

African (AFR) AF: 0.143 AC: 3342 AN: 23352

American (AMR) AF: 0.00673 AC: 219 AN: 32542

Ashkenazi Jewish (ASJ) AF: 0.000220 AC: 4 AN: 18165

East Asian (EAS) AF: 0.00 AC: 0 AN: 28634

South Asian (SAS) AF: 0.000202 AC: 10 AN: 49553

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39030

Middle Eastern (MID) AF: 0.00709 AC: 25 AN: 3525

European-Non Finnish (NFE) AF: 0.000138 AC: 99 AN: 715905

Other (OTH) AF: 0.00859 AC: 355 AN: 41309

GnomAD4 genome AF: 0.0370 AC: 4163 AN: 112365 Hom.: 200 Cov.: 25 AF XY: 0.0322 AC XY: 1113 AN XY: 34579

African (AFR) AF: 0.127 AC: 3934 AN: 30910

American (AMR) AF: 0.0148 AC: 159 AN: 10755

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.000734 AC: 2 AN: 2725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000264 AC: 14 AN: 53093

Other (OTH) AF: 0.0352 AC: 54 AN: 1535

Alfa AF: 0.0277 Hom.: 88

Bravo AF: 0.0430

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.37
DANN	Benign	0.47
PhyloP100		-3.2
PromoterAI		0.0012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs191116415; hg19: chrX-153170742;