12-49965063-C-G

Variant names:

• chr12-49965063-C-G
• rs41495048
• NM_001651.4:c.684C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001651.4(AQP5):​c.684C>G​(p.Asn228Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AQP5 NM_001651.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.211
• Publications: 0 publications found

Genes affected

AQP5 (HGNC:638): (aquaporin 5) Aquaporin 5 (AQP5) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 5 plays a role in the generation of saliva, tears and pulmonary secretions. AQP0, AQP2, AQP5, and AQP6 are closely related and all map to 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP5	NM_001651.4	c.684C>G	p.Asn228Lys	missense_variant	Exon 4 of 4	ENST00000293599.7	NP_001642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP5	ENST00000293599.7	c.684C>G	p.Asn228Lys	missense_variant	Exon 4 of 4	1	NM_001651.4	ENSP00000293599.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.21
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.21
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.069
MutPred		0.49		Gain of methylation at N228 (P = 0.0122);
MVP		0.79
MPC		0.42
ClinPred		0.036	T
GERP RS		3.3
Varity_R		0.26
gMVP		0.20
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41495048; hg19: chr12-50358846;