12-49950833-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000486.6(AQP2):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,174 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AQP2 NM_000486.6 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49950833-G-T is Pathogenic according to our data. Variant chr12-49950833-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 998050.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP2	NM_000486.6	c.3G>T	p.Met1?	start_lost	1/4	ENST00000199280.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP2	ENST00000199280.4	c.3G>T	p.Met1?	start_lost	1/4	1	NM_000486.6	P1
AQP2	ENST00000550862.1	c.3G>T	p.Met1?	start_lost	1/3	5
AQP2	ENST00000551526.5	c.3G>T	p.Met1?	start_lost, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250878 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459174 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

research

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

May 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.037	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.28	B;.
Vest4		0.98
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0227);Gain of catalytic residue at M1 (P = 0.0227);
MVP		0.89
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.61
gMVP		0.33

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: rs1288385043; hg19: chr12-50344616;