rs61733029

Variant names:

• chr12-49950869-G-A
• rs61733029
• NM_000486.6:c.39G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000486.6(AQP2):​c.39G>A​(p.Val13Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,613,494 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (51 hom.)
• Consequence: AQP2 NM_000486.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.55
• Publications: 2 publications found

Genes affected

AQP2 (HGNC:634): (aquaporin 2) This gene encodes a water channel protein located in the kidney collecting tubule. It belongs to the MIP/aquaporin family, some members of which are clustered together on chromosome 12q13. Mutations in this gene have been linked to autosomal dominant and recessive forms of nephrogenic diabetes insipidus. [provided by RefSeq, Oct 2008]

AQP2 Gene-Disease associations (from GenCC):

• diabetes insipidus, nephrogenic, autosomal

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• nephrogenic diabetes insipidus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-49950869-G-A is Benign according to our data. Variant chr12-49950869-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0055 (838/152400) while in subpopulation AMR AF = 0.0104 (160/15314). AF 95% confidence interval is 0.00913. There are 2 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000486.6. 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
	AQP2	NM_000486.6	MANE Select	c.39G>A	p.Val13Val	synonymous	Exon 1 of 4	NP_000477.1	P41181

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	ENST00000199280.4	TSL:1 MANE Select	c.39G>A	p.Val13Val	synonymous	Exon 1 of 4	ENSP00000199280.3	P41181
	AQP2	ENST00000550862.1	TSL:5	c.39G>A	p.Val13Val	synonymous	Exon 1 of 3	ENSP00000450022.1	F8VPL3
	AQP2	ENST00000551526.5	TSL:5	n.39G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152282 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00704

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00590 AC: 1482 AN: 251302 AF XY: 0.00637

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00753

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00672 AC: 9818 AN: 1461094 Hom.: 51 Cov.: 31 AF XY: 0.00690 AC XY: 5013 AN XY: 726668

African (AFR) AF: 0.00131 AC: 44 AN: 33468

American (AMR) AF: 0.00653 AC: 292 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 227 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00815 AC: 703 AN: 86254

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53328

Middle Eastern (MID) AF: 0.0350 AC: 202 AN: 5764

European-Non Finnish (NFE) AF: 0.00698 AC: 7757 AN: 1111422

Other (OTH) AF: 0.00797 AC: 481 AN: 60358

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152400 Hom.: 2 Cov.: 33 AF XY: 0.00535 AC XY: 399 AN XY: 74538

African (AFR) AF: 0.00103 AC: 43 AN: 41602

American (AMR) AF: 0.0104 AC: 160 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00765 AC: 37 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10630

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00704 AC: 479 AN: 68036

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00738 Hom.: 3

Bravo AF: 0.00634

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0105

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Diabetes insipidus, nephrogenic, autosomal (2)
-	-	2	not specified (2)
-	-	1	Nephrogenic diabetes insipidus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.6
DANN	Benign	0.80
PhyloP100		1.6
PromoterAI		-0.029	Neutral
Mutation Taster		=99/1	polymorphism

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: rs61733029; hg19: chr12-50344652;