rs104894339

Variant names:

• chr12-49955577-C-G
• rs104894339
• NM_000486.6:c.785C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-49955577-C-G
• chr12-49955577-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000486.6(AQP2):​c.785C>G​(p.Pro262Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,433,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P262L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AQP2 NM_000486.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86
• Publications: 17 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)

ENSG00000257378 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a mutagenesis_site No effect on expression at the apical cell membrane. (size 0) in uniprot entity AQP2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49955577-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36839992).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	NM_000486.6	MANE Select	c.785C>G	p.Pro262Arg	missense	Exon 4 of 4	NP_000477.1
	AQP5-AS1	NR_110590.1		n.257-1229G>C		intron	N/A
	AQP5-AS1	NR_110591.1		n.118-3489G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	ENST00000199280.4	TSL:1 MANE Select	c.785C>G	p.Pro262Arg	missense	Exon 4 of 4	ENSP00000199280.3
	AQP5-AS1	ENST00000550530.1	TSL:3	n.118-3489G>C		intron	N/A
	AQP2	ENST00000551526.5	TSL:5	n.631+154C>G		intron	N/A	ENSP00000447148.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000499 AC: 1 AN: 200378 AF XY: 0.00000904

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: 0.0000691

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433862 Hom.: 0 Cov.: 66 AF XY: 0.00000140 AC XY: 1 AN XY: 712128

African (AFR) AF: 0.00 AC: 0 AN: 32910

American (AMR) AF: 0.00 AC: 0 AN: 42140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 38470

South Asian (SAS) AF: 0.00 AC: 0 AN: 83704

European-Finnish (FIN) AF: 0.0000225 AC: 1 AN: 44426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102426

Other (OTH) AF: 0.00 AC: 0 AN: 59380

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.27
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.052	T
Polyphen		0.97	D
Vest4		0.31
MutPred		0.37		Gain of MoRF binding (P = 0.0081)
MVP		0.94
MPC		1.2
ClinPred		0.72	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.91
Mutation Taster		=57/43	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: rs104894339; hg19: chr12-50349360;