2-240692261-C-T

Variant names:

• chr2-240692261-C-T
• rs201167811
• NM_198998.3:c.311C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198998.3(AQP12A):​c.311C>T​(p.Ala104Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,578,628 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (2 hom., cov: 29)
  • Exomes 𝑓: 0.000038 (6 hom.)
• Consequence: AQP12A NM_198998.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.474
• Publications: 1 publications found

Genes affected

AQP12A (HGNC:19941): (aquaporin 12A) Predicted to enable channel activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.064825535).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198998.3. 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
	AQP12A	NM_198998.3	MANE Select	c.311C>T	p.Ala104Val	missense	Exon 2 of 4	NP_945349.1	Q8IXF9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP12A	ENST00000337801.9	TSL:1 MANE Select	c.311C>T	p.Ala104Val	missense	Exon 2 of 4	ENSP00000337144.4	Q8IXF9

Frequencies

GnomAD3 genomes AF: 0.0000414 AC: 6 AN: 145034 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.0000264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000728

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000422

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000420 AC: 10 AN: 238318 AF XY: 0.0000692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000679

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.0000377 AC: 54 AN: 1433504 Hom.: 6 Cov.: 40 AF XY: 0.0000434 AC XY: 31 AN XY: 713598

African (AFR) AF: 0.00 AC: 0 AN: 31674

American (AMR) AF: 0.0000517 AC: 2 AN: 38710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.0000802 AC: 3 AN: 37390

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4812

European-Non Finnish (NFE) AF: 0.0000245 AC: 27 AN: 1100400

Other (OTH) AF: 0.000321 AC: 19 AN: 59122

GnomAD4 genome AF: 0.0000413 AC: 6 AN: 145124 Hom.: 2 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 70720

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000264 AC: 1 AN: 37922

American (AMR) AF: 0.0000728 AC: 1 AN: 13740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.000423 AC: 2 AN: 4730

South Asian (SAS) AF: 0.00 AC: 0 AN: 4556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67114

Other (OTH) AF: 0.00 AC: 0 AN: 2014

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000424 AC: 5

EpiCase AF: 0.0000549

EpiControl AF: 0.0000598

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	Benign	0.087
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.66
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.39	N
PhyloP100		-0.47
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.053
Sift	Benign	0.53	T
Sift4G	Benign	0.33	T
Polyphen		0.066	B
Vest4		0.10
MutPred		0.51		Loss of ubiquitination at K102 (P = 0.1166)
MVP		0.048
MPC		0.35
ClinPred		0.011	T
GERP RS		-2.0
PromoterAI		-0.00040	Neutral
Varity_R		0.029
gMVP		0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201167811; hg19: chr2-241631678;