rs104894341

Positions:

• chr12-49954672-G-A
• chr12-49954672-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000486.6(AQP2):​c.568G>A​(p.Ala190Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AQP2 NM_000486.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.77

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)

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Aquaporin-2 (size 270) in uniprot entity AQP2_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_000486.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 12-49954672-G-A is Pathogenic according to our data. Variant chr12-49954672-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6	c.568G>A	p.Ala190Thr	missense_variant	3/4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110591.1	n.118-2584C>T		intron_variant, non_coding_transcript_variant
AQP5-AS1	NR_110590.1	n.257-324C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.568G>A	p.Ala190Thr	missense_variant	3/4	1	NM_000486.6	ENSP00000199280	P1
AQP5-AS1	ENST00000550530.1	n.118-2584C>T		intron_variant, non_coding_transcript_variant		3
	ENST00000552806.1	n.542-15C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	0.36	A
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.0030	B;.
Vest4		0.55
MutPred		0.96		Gain of phosphorylation at A190 (P = 0.0454);.;
MVP		0.99
MPC		0.52
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.67
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894341; hg19: chr12-50348455; COSMIC: COSV52230586; COSMIC: COSV52230586;