12-49974417-C-G

Position:

• chr12-49974417-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001652.4(AQP6):​c.496C>G​(p.Arg166Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,756 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: AQP6 NM_001652.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.72

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]

LOC105369764 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053281486).
• BP6: Variant 12-49974417-C-G is Benign according to our data. Variant chr12-49974417-C-G is described in ClinVar as [Benign]. Clinvar id is 785405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2074/152308) while in subpopulation AFR AF= 0.0477 (1981/41552). AF 95% confidence interval is 0.0459. There are 48 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP6	NM_001652.4	c.496C>G	p.Arg166Gly	missense_variant	2/4	ENST00000315520.10	NP_001643.2
LOC105369764	XR_001749143.2	n.208+881G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP6	ENST00000315520.10	c.496C>G	p.Arg166Gly	missense_variant	2/4	1	NM_001652.4	ENSP00000320247	P1
AQP6	ENST00000489786.5	n.2915C>G		non_coding_transcript_exon_variant	5/7	1
AQP6	ENST00000551733.5	c.-27C>G		5_prime_UTR_variant	4/6	3		ENSP00000449830

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2070 AN: 152190 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00366 AC: 919 AN: 250950 Hom.: 20 AF XY: 0.00272 AC XY: 369 AN XY: 135638

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00147 AC: 2155 AN: 1461448 Hom.: 48 Cov.: 32 AF XY: 0.00128 AC XY: 931 AN XY: 727060

Gnomad4 AFR exome AF: 0.0493

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0136 AC: 2074 AN: 152308 Hom.: 48 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74480

Gnomad4 AFR AF: 0.0477

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.000828 Hom.: 6

Bravo AF: 0.0162

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00470 AC: 571

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Apr 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	.;D
MetaRNN	Benign	0.0053	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;D
Vest4		0.29
MVP		0.97
MPC		0.80
ClinPred		0.056	T
GERP RS		3.4
Varity_R		0.73
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114066000; hg19: chr12-50368200;