12-49951129-GA-TC

Variant names:

• chr12-49951129-GA-TC
• NM_000486.6:c.299_300delGAinsTC
• AQP2 p.Gly100Val

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1_Very_Strong PM1 PM5 PP3

The NM_000486.6(AQP2):​c.299_300delGAinsTC​(p.Gly100Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G100R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AQP2 NM_000486.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00
• 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: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• nephrogenic diabetes insipidus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript NM_000486.6 (AQP2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a chain Aquaporin-2 (size 270) in uniprot entity AQP2_HUMAN there are 29 pathogenic changes around while only 8 benign (78%) in NM_000486.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49951128-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1319413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.299_300delGAinsTC	p.Gly100Val	missense	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.299_300delGAinsTC	p.Gly100Val	missense	N/A	ENSP00000199280.3	P41181
	AQP2	ENST00000550862.1	TSL:5	c.299_300delGAinsTC	p.Gly100Val	missense	N/A	ENSP00000450022.1	F8VPL3
	AQP2	ENST00000551526.5	TSL:5	n.299_300delGAinsTC		non_coding_transcript_exon	Exon 1 of 6	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-50344912;