12-49962151-T-G

Position:

• chr12-49962151-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001651.4(AQP5):​c.134T>G​(p.Ile45Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AQP5 NM_001651.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.19

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)

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 12-49962151-T-G is Pathogenic according to our data. Variant chr12-49962151-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 65480.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP5	NM_001651.4	c.134T>G	p.Ile45Ser	missense_variant	1/4	ENST00000293599.7	NP_001642.1
AQP5-AS1	NR_110591.1	n.117+516A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP5	ENST00000293599.7	c.134T>G	p.Ile45Ser	missense_variant	1/4	1	NM_001651.4	ENSP00000293599	P1
AQP5-AS1	ENST00000550530.1	n.117+516A>C		intron_variant, non_coding_transcript_variant		3
AQP5-AS1	ENST00000550214.1	n.258+516A>C		intron_variant, non_coding_transcript_variant		2
AQP5-AS1	ENST00000552379.1	n.256+516A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Palmoplantar keratoderma, Bothnian type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.81
Sift	Benign	0.043	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.71		Gain of glycosylation at I45 (P = 0.0247);
MVP		0.94
MPC		1.4
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.75
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123055; hg19: chr12-50355934;