12-49955307-A-G

Variant names:

• chr12-49955307-A-G
• rs410837
• NM_000486.6:c.607-92A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
AQP2	NM_000486.6	c.607-92A>G		intron_variant	Intron 3 of 3	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.257-959T>C		intron_variant	Intron 1 of 2
AQP5-AS1	NR_110591.1	n.118-3219T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.607-92A>G		intron_variant	Intron 3 of 3	1	NM_000486.6	ENSP00000199280.3

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

African (AFR) AF: 0.609 AC: 14575 AN: 23934

American (AMR) AF: 0.979 AC: 25596 AN: 26132

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 18893 AN: 18904

East Asian (EAS) AF: 0.997 AC: 34561 AN: 34650

South Asian (SAS) AF: 0.999 AC: 65066 AN: 65124

European-Finnish (FIN) AF: 1.00 AC: 44838 AN: 44838

Middle Eastern (MID) AF: 0.984 AC: 3416 AN: 3470

European-Non Finnish (NFE) AF: 0.999 AC: 817365 AN: 817786

Other (OTH) AF: 0.975 AC: 45507 AN: 46666

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

African (AFR) AF: 0.616 AC: 25568 AN: 41510

American (AMR) AF: 0.962 AC: 14733 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3470 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5149 AN: 5168

South Asian (SAS) AF: 0.998 AC: 4824 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67978 AN: 68038

Other (OTH) AF: 0.929 AC: 1962 AN: 2112

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

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Diabetes insipidus, nephrogenic, autosomal Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.68
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs410837; hg19: chr12-50349090;