NM_198334.3:c.1148C>G

Variant names:

• chr11-62631032-G-C
• rs879255642
• NM_198334.3:c.1148C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_198334.3(GANAB):​c.1148C>G​(p.Thr383Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GANAB NM_198334.3 missense, splice_region
• Scores: Splicing: ADA: 0.9428
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.91
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• polycystic kidney disease 3 with or without polycystic liver disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 11-62631032-G-C is Pathogenic according to our data. Variant chr11-62631032-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 253130.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198334.3. 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
	GANAB	NM_198334.3	MANE Select	c.1148C>G	p.Thr383Arg	missense splice_region	Exon 10 of 24	NP_938148.1	Q14697-1
	GANAB	NM_198335.4		c.1214C>G	p.Thr405Arg	missense splice_region	Exon 11 of 25	NP_938149.2	Q14697-2
	GANAB	NM_001278192.2		c.872C>G	p.Thr291Arg	missense splice_region	Exon 8 of 22	NP_001265121.1	E9PKU7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GANAB	ENST00000356638.8	TSL:1 MANE Select	c.1148C>G	p.Thr383Arg	missense splice_region	Exon 10 of 24	ENSP00000349053.3	Q14697-1
	GANAB	ENST00000346178.8	TSL:1	c.1214C>G	p.Thr405Arg	missense splice_region	Exon 11 of 25	ENSP00000340466.4	Q14697-2
	GANAB	ENST00000540933.5	TSL:1	c.857C>G	p.Thr286Arg	missense splice_region	Exon 9 of 23	ENSP00000442962.1	F5H6X6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	POLYCYSTIC KIDNEY DISEASE 3 WITHOUT POLYCYSTIC LIVER DISEASE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		9.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.89		Gain of methylation at T383 (P = 0.0203)
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.66
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: rs879255642; hg19: chr11-62398504;