chr12-49955307-A-G

Position:

• chr12-49955307-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000486.6(AQP2):​c.607-92A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.977 in 1,233,768 control chromosomes in the GnomAD database, including 593,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (62498 hom., cov: 33)
  • Exomes 𝑓: 0.99 (531046 hom.)
• Consequence: AQP2 NM_000486.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.33

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-49955307-A-G is Benign according to our data. Variant chr12-49955307-A-G is described in ClinVar as [Benign]. Clinvar id is 1178280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6	c.607-92A>G		intron_variant		ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110591.1	n.118-3219T>C		intron_variant, non_coding_transcript_variant
AQP5-AS1	NR_110590.1	n.257-959T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.607-92A>G		intron_variant		1	NM_000486.6	ENSP00000199280	P1
AQP5-AS1	ENST00000550530.1	n.118-3219T>C		intron_variant, non_coding_transcript_variant		3
	ENST00000552806.1	n.541+278T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135419 AN: 152146 Hom.: 62465 Cov.: 33

Gnomad AFR AF: 0.616

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.928

GnomAD4 exome AF: 0.989 AC: 1069817 AN: 1081504 Hom.: 531046 AF XY: 0.991 AC XY: 534533 AN XY: 539634

Gnomad4 AFR exome AF: 0.609

Gnomad4 AMR exome AF: 0.979

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 0.997

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.975

GnomAD4 genome AF: 0.890 AC: 135502 AN: 152264 Hom.: 62498 Cov.: 33 AF XY: 0.894 AC XY: 66525 AN XY: 74454

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.962

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.998

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.929

Alfa AF: 0.932 Hom.: 8406

Bravo AF: 0.874

Asia WGS AF: 0.978 AC: 3400 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Diabetes insipidus, nephrogenic, autosomal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs410837; hg19: chr12-50349090;