X-153905643-T-C

Variant names:

• chrX-153905643-T-C
• rs104894759
• NM_000054.7:c.137T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_000054.7(AVPR2):​c.137T>C​(p.Ile46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,097,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I46K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0320
• Publications: 7 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 -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153905643-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10852.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03805816).
• BS2: High AC in GnomAdExome4 at 18 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVPR2	NM_000054.7	MANE Select	c.137T>C	p.Ile46Thr	missense	Exon 3 of 4	NP_000045.1
	AVPR2	NM_001146151.3		c.137T>C	p.Ile46Thr	missense	Exon 3 of 3	NP_001139623.1
	AVPR2	NR_027419.2		n.466-376T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVPR2	ENST00000646375.2	MANE Select	c.137T>C	p.Ile46Thr	missense	Exon 3 of 4	ENSP00000496396.1
	AVPR2	ENST00000337474.5	TSL:1	c.137T>C	p.Ile46Thr	missense	Exon 2 of 3	ENSP00000338072.5
	AVPR2	ENST00000370049.1	TSL:1	c.137T>C	p.Ile46Thr	missense	Exon 2 of 2	ENSP00000359066.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.0000168 AC: 3 AN: 178801 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000379

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1097340 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 4 AN XY: 363080

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40115

Middle Eastern (MID) AF: 0.000488 AC: 2 AN: 4100

European-Non Finnish (NFE) AF: 0.0000178 AC: 15 AN: 841854

Other (OTH) AF: 0.0000217 AC: 1 AN: 46055

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes insipidus, nephrogenic, X-linked;C1845202:Nephrogenic syndrome of inappropriate antidiuresis Uncertain:1

May 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.71
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-0.032
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.037
Sift	Benign	0.99	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.59		Loss of stability (P = 0.0096)
MVP		0.98
MPC		0.63
ClinPred		0.025	T
GERP RS		0.56
Varity_R		0.061
gMVP		0.65
Mutation Taster		=33/67	disease causing

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: rs104894759; hg19: chrX-153171097;