chr12-49973572-C-A

Variant names:

• chr12-49973572-C-A
• rs374093263
• NM_001652.4:c.399C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001652.4(AQP6):​c.399C>A​(p.Asn133Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,598,334 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: AQP6 NM_001652.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.18
• Publications: 0 publications found

Genes affected

AQP6 (HGNC:639): (aquaporin 6) The protein encoded by this gene is an aquaporin protein, which functions as a water channel in cells. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). This protein is specific for the kidney. This gene and related family members AQP0, AQP2, and AQP5 reside in a cluster on chromosome 12q13. [provided by RefSeq, Jul 2008]

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

LOC105369764 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001652.4. 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
	AQP6	NM_001652.4	MANE Select	c.399C>A	p.Asn133Lys	missense	Exon 1 of 4	NP_001643.2	Q13520

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP6	ENST00000315520.10	TSL:1 MANE Select	c.399C>A	p.Asn133Lys	missense	Exon 1 of 4	ENSP00000320247.5	Q13520
	AQP6	ENST00000489786.5	TSL:1	n.2412C>A		non_coding_transcript_exon	Exon 4 of 7
	AQP6	ENST00000861814.1		c.399C>A	p.Asn133Lys	missense	Exon 1 of 4	ENSP00000531873.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000458 AC: 1 AN: 218546 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446174 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717936

African (AFR) AF: 0.00 AC: 0 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 42094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 38968

South Asian (SAS) AF: 0.00 AC: 0 AN: 84934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104066

Other (OTH) AF: 0.0000167 AC: 1 AN: 59786

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	1.2
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-1.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.62		Gain of methylation at N133 (P = 0.009)
MVP		0.89
MPC		0.92
ClinPred		0.99	D
GERP RS		-5.1
PromoterAI		-0.016	Neutral
Varity_R		0.93
gMVP		0.75
Mutation Taster		=76/24	polymorphism

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: rs374093263; hg19: chr12-50367355;