chr12-49951172-G-A

Variant names:

• chr12-49951172-G-A
• rs35400945
• NM_000486.6:c.342G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000486.6(AQP2):​c.342G>A​(p.Gly114Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,605,498 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: AQP2 NM_000486.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.755
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-49951172-G-A is Benign according to our data. Variant chr12-49951172-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.755 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1829/152340) while in subpopulation AFR AF = 0.0419 (1742/41568). AF 95% confidence interval is 0.0403. There are 40 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR,AD 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.342G>A	p.Gly114Gly	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.342G>A	p.Gly114Gly	synonymous	Exon 1 of 4	ENSP00000199280.3	P41181
	AQP2	ENST00000550862.1	TSL:5	c.342G>A	p.Gly114Gly	synonymous	Exon 1 of 3	ENSP00000450022.1	F8VPL3
	AQP2	ENST00000551526.5	TSL:5	n.342G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1826 AN: 152222 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00310 AC: 743 AN: 239856 AF XY: 0.00216

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00128 AC: 1853 AN: 1453158 Hom.: 38 Cov.: 30 AF XY: 0.00108 AC XY: 777 AN XY: 721988

African (AFR) AF: 0.0442 AC: 1474 AN: 33372

American (AMR) AF: 0.00228 AC: 101 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25586

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84886

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52196

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5730

European-Non Finnish (NFE) AF: 0.0000740 AC: 82 AN: 1107518

Other (OTH) AF: 0.00310 AC: 186 AN: 60048

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152340 Hom.: 40 Cov.: 33 AF XY: 0.0119 AC XY: 886 AN XY: 74486

African (AFR) AF: 0.0419 AC: 1742 AN: 41568

American (AMR) AF: 0.00359 AC: 55 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00598 Hom.: 15

Bravo AF: 0.0140

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	-0.48
CADD	Benign	7.2
DANN	Benign	0.81
PhyloP100		-0.76
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	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: rs35400945; hg19: chr12-50344955;