rs879255641

Variant names:

• chr11-62629280-CCT-C
• rs879255641
• NM_198334.3:c.1848_1849delAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_198334.3(GANAB):​c.1848_1849delAG​(p.Asp618GlnfsTer77) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GANAB NM_198334.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-62629280-CCT-C is Pathogenic according to our data. Variant chr11-62629280-CCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 253129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1848_1849delAG	p.Asp618GlnfsTer77	frameshift	Exon 16 of 24	NP_938148.1	Q14697-1
	GANAB	NM_198335.4		c.1914_1915delAG	p.Asp640GlnfsTer77	frameshift	Exon 17 of 25	NP_938149.2	Q14697-2
	GANAB	NM_001278192.2		c.1572_1573delAG	p.Asp526GlnfsTer77	frameshift	Exon 14 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.1848_1849delAG	p.Asp618GlnfsTer77	frameshift	Exon 16 of 24	ENSP00000349053.3	Q14697-1
	GANAB	ENST00000346178.8	TSL:1	c.1914_1915delAG	p.Asp640GlnfsTer77	frameshift	Exon 17 of 25	ENSP00000340466.4	Q14697-2
	GANAB	ENST00000540933.5	TSL:1	c.1557_1558delAG	p.Asp521GlnfsTer77	frameshift	Exon 15 of 23	ENSP00000442962.1	F5H6X6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Polycystic kidney disease 3 with or without polycystic liver disease (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255641; hg19: chr11-62396752;