Variant chr11-62626633-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_198334.3(GANAB):c.2449C>T(p.Arg817Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,858 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GANAB
NM_198334.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.79

Variant links:

Genes affected

GANAB (HGNC:4138): (glucosidase II alpha subunit) This gene encodes the alpha subunit of glucosidase II and a member of the glycosyl hydrolase 31 family of proteins. The heterodimeric enzyme glucosidase II plays a role in protein folding and quality control by cleaving glucose residues from immature glycoproteins in the endoplasmic reticulum. Expression of the encoded protein is elevated in lung tumor tissue and in response to UV irradiation. Mutations in this gene cause autosomal-dominant polycystic kidney and liver disease. [provided by RefSeq, Jul 2016]

GANAB links:

GANAB (HGNC:):

GANAB links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GANAB. . Gene score misZ 2.2404 (greater than the threshold 3.09). Trascript score misZ 3.2543 (greater than threshold 3.09). GenCC has associacion of gene with polycystic kidney disease 3 with or without polycystic liver disease, autosomal dominant polycystic kidney disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

PP5

Variant 11-62626633-G-A is Pathogenic according to our data. Variant chr11-62626633-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62626633-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GANAB	NM_198334.3 linkuse as main transcript	c.2449C>T	p.Arg817Trp	missense_variant	21/24	ENST00000356638.8	NP_938148.1	Q14697-1V9HWJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GANAB	ENST00000356638.8 linkuse as main transcript	c.2449C>T	p.Arg817Trp	missense_variant	21/24	1	NM_198334.3	ENSP00000349053.3		Q14697-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459858

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

POLYCYSTIC KIDNEY DISEASE 3 WITH POLYCYSTIC LIVER DISEASE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 22, 2018

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2024

Published functional studies suggest a damaging effect on cell surface localization of polycystin-1 (PMID: 27259053); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34310849, 27259053, 30484248, 37703354, 32378324, 34357571, 30652979) -

Polycystic kidney disease 3 with or without polycystic liver disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;.;.;D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.5

.;.;.;H;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.6

D;D;.;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.019

D;D;.;D;D

Sift4G

Uncertain

0.023

D;D;.;D;D

Polyphen

1.0

D;.;.;D;D

Vest4

0.93

MutPred

0.49

.;.;.;Loss of disorder (P = 0.0196);.;

MVP

0.95

MPC

0.82

ClinPred

0.99

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over