11-62626342-C-T

Position:

• chr11-62626342-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_198334.3(GANAB):​c.2617G>A​(p.Val873Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GANAB NM_198334.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.079221964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GANAB	NM_198334.3	c.2617G>A	p.Val873Ile	missense_variant	22/24	ENST00000356638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GANAB	ENST00000356638.8	c.2617G>A	p.Val873Ile	missense_variant	22/24	1	NM_198334.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with GANAB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 895 of the GANAB protein (p.Val895Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.059	.;.;.;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.73	T;T;.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.079	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.41	.;.;.;N;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.30	N;N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.56	T;T;.;T;T
Sift4G	Benign	0.55	T;T;.;T;T
Polyphen		0.0020	B;.;.;B;B
Vest4		0.073
MutPred		0.27		.;.;.;Gain of catalytic residue at S875 (P = 0.0954);.;
MVP		0.23
MPC		0.17
ClinPred		0.15	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-62393814;