rs201419746

Variant names:

• chrX-153905169-C-A
• rs201419746
• NM_000054.7:c.24C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153905169-C-A
• chrX-153905169-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000054.7(AVPR2):​c.24C>A​(p.Ser8Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,020 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AVPR2 NM_000054.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002077
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -9.59
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP7: Synonymous conserved (PhyloP=-9.59 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.24C>A	p.Ser8Ser	splice_region_variant, synonymous_variant	Exon 2 of 4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.24C>A	p.Ser8Ser	splice_region_variant, synonymous_variant	Exon 2 of 3		NP_001139623.1
AVPR2	NR_027419.2	n.464C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.24C>A	p.Ser8Ser	splice_region_variant, synonymous_variant	Exon 2 of 4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3901G>T		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098020 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363456

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841994

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0010
DANN	Benign	0.79
PhyloP100		-9.6
PromoterAI		0.043	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.044
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: rs201419746; hg19: chrX-153170623;