12-49951193-G-A

Variant names:

• chr12-49951193-G-A
• rs3741559
• NM_000486.6:c.360+3G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000486.6(AQP2):​c.360+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,600,584 control chromosomes in the GnomAD database, including 30,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2535 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28003 hom.)
• Consequence: AQP2 NM_000486.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003329
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.58
• Publications: 27 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-49951193-G-A is Benign according to our data. Variant chr12-49951193-G-A is described in ClinVar as Benign. ClinVar VariationId is 256243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 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.360+3G>A		splice_region intron	N/A	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.360+3G>A		splice_region intron	N/A	ENSP00000199280.3	P41181
	AQP2	ENST00000550862.1	TSL:5	c.360+3G>A		splice_region intron	N/A	ENSP00000450022.1	F8VPL3
	AQP2	ENST00000551526.5	TSL:5	n.360+3G>A		splice_region intron	N/A	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25929 AN: 152132 Hom.: 2539 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.197 AC: 45710 AN: 232494 AF XY: 0.206

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.370

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.188 AC: 272814 AN: 1448332 Hom.: 28003 Cov.: 33 AF XY: 0.193 AC XY: 138660 AN XY: 719146

African (AFR) AF: 0.123 AC: 4103 AN: 33352

American (AMR) AF: 0.105 AC: 4586 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6206 AN: 25258

East Asian (EAS) AF: 0.367 AC: 14509 AN: 39548

South Asian (SAS) AF: 0.315 AC: 26440 AN: 83898

European-Finnish (FIN) AF: 0.155 AC: 7971 AN: 51532

Middle Eastern (MID) AF: 0.293 AC: 1653 AN: 5636

European-Non Finnish (NFE) AF: 0.176 AC: 194908 AN: 1105404

Other (OTH) AF: 0.208 AC: 12438 AN: 59876

GnomAD4 genome AF: 0.170 AC: 25920 AN: 152252 Hom.: 2535 Cov.: 33 AF XY: 0.173 AC XY: 12841 AN XY: 74412

African (AFR) AF: 0.123 AC: 5125 AN: 41564

American (AMR) AF: 0.130 AC: 1991 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3472

East Asian (EAS) AF: 0.358 AC: 1852 AN: 5170

South Asian (SAS) AF: 0.321 AC: 1551 AN: 4826

European-Finnish (FIN) AF: 0.155 AC: 1638 AN: 10598

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12217 AN: 68006

Other (OTH) AF: 0.189 AC: 400 AN: 2114

Alfa AF: 0.180 Hom.: 11900

Bravo AF: 0.161

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Diabetes insipidus, nephrogenic, autosomal (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Nephrogenic diabetes insipidus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.76
PhyloP100		1.6
PromoterAI		0.023	Neutral
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs3741559; hg19: chr12-50344976; COSMIC: COSV52229613; COSMIC: COSV52229613;