chr12-49954295-T-C

Variant names:

• chr12-49954295-T-C
• rs426496
• NM_000486.6:c.501T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000486.6(AQP2):​c.501T>C​(p.Ser167Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 1,608,946 control chromosomes in the GnomAD database, including 498,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40074 hom., cov: 31)
  • Exomes 𝑓: 0.79 (458430 hom.)
• Consequence: AQP2 NM_000486.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.37
• Publications: 22 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]

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-49954295-T-C is Benign according to our data. Variant chr12-49954295-T-C is described in ClinVar as Benign. ClinVar VariationId is 504917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

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.501T>C	p.Ser167Ser	synonymous	Exon 2 of 4	NP_000477.1
	AQP5-AS1	NR_110590.1		n.310A>G		non_coding_transcript_exon	Exon 2 of 3
	AQP5-AS1	NR_110591.1		n.118-2207A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	ENST00000199280.4	TSL:1 MANE Select	c.501T>C	p.Ser167Ser	synonymous	Exon 2 of 4	ENSP00000199280.3
	AQP2	ENST00000550862.1	TSL:5	c.501T>C	p.Ser167Ser	synonymous	Exon 2 of 3	ENSP00000450022.1
	AQP2	ENST00000551526.5	TSL:5	n.501T>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000447148.1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107887 AN: 151888 Hom.: 40036 Cov.: 31

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.718

GnomAD2 exomes AF: 0.766 AC: 188673 AN: 246408 AF XY: 0.765

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.875

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.627

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.790 AC: 1151098 AN: 1456940 Hom.: 458430 Cov.: 68 AF XY: 0.788 AC XY: 570946 AN XY: 724942

African (AFR) AF: 0.470 AC: 15734 AN: 33472

American (AMR) AF: 0.866 AC: 38684 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 19117 AN: 26126

East Asian (EAS) AF: 0.633 AC: 25108 AN: 39696

South Asian (SAS) AF: 0.698 AC: 60206 AN: 86240

European-Finnish (FIN) AF: 0.844 AC: 41240 AN: 48872

Middle Eastern (MID) AF: 0.676 AC: 3897 AN: 5766

European-Non Finnish (NFE) AF: 0.811 AC: 901374 AN: 1111754

Other (OTH) AF: 0.758 AC: 45738 AN: 60338

GnomAD4 genome AF: 0.710 AC: 107978 AN: 152006 Hom.: 40074 Cov.: 31 AF XY: 0.713 AC XY: 52979 AN XY: 74306

African (AFR) AF: 0.484 AC: 20036 AN: 41426

American (AMR) AF: 0.819 AC: 12525 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2533 AN: 3472

East Asian (EAS) AF: 0.639 AC: 3287 AN: 5142

South Asian (SAS) AF: 0.694 AC: 3341 AN: 4816

European-Finnish (FIN) AF: 0.844 AC: 8934 AN: 10586

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54895 AN: 67960

Other (OTH) AF: 0.722 AC: 1521 AN: 2108

Alfa AF: 0.771 Hom.: 21725

Bravo AF: 0.702

Asia WGS AF: 0.737 AC: 2563 AN: 3478

EpiCase AF: 0.801

EpiControl AF: 0.795

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.55
PhyloP100		-4.4
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs426496; hg19: chr12-50348078; COSMIC: COSV52229985; COSMIC: COSV52229985;