rs398122983

Variant names:

• chr19-40692307-AAGGGCCC-A
• rs398122983
• NM_024876.4:c.1356_1362delGGGCCCT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_024876.4(COQ8B):​c.1356_1362delGGGCCCT​(p.Gln452HisfsTer260) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COQ8B NM_024876.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 5.77
• Publications: 5 publications found

Genes affected

COQ8B (HGNC:19041): (coenzyme Q8B) This gene encodes a protein with two copies of a domain found in protein kinases. The encoded protein has a complete protein kinase catalytic domain, and a truncated domain that contains only the active and binding sites of the protein kinase domain, however, it is not known whether the protein has any kinase activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

COQ8B Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• nephrotic syndrome, type 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-40692307-AAGGGCCC-A is Pathogenic according to our data. Variant chr19-40692307-AAGGGCCC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 91851.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024876.4. 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
	COQ8B	NM_024876.4	MANE Select	c.1356_1362delGGGCCCT	p.Gln452HisfsTer260	frameshift	Exon 15 of 15	NP_079152.3
	COQ8B	NM_001142555.3		c.1233_1239delGGGCCCT	p.Gln411HisfsTer260	frameshift	Exon 14 of 14	NP_001136027.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ8B	ENST00000324464.8	TSL:1 MANE Select	c.1356_1362delGGGCCCT	p.Gln452HisfsTer260	frameshift	Exon 15 of 15	ENSP00000315118.3
	COQ8B	ENST00000243583.10	TSL:1	c.1233_1239delGGGCCCT	p.Gln411HisfsTer260	frameshift	Exon 14 of 14	ENSP00000243583.5
	COQ8B	ENST00000871658.1		c.1401_1407delGGGCCCT	p.Gln467HisfsTer261	frameshift	Exon 15 of 15	ENSP00000541717.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Nephrotic syndrome, type 9 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398122983; hg19: chr19-41198212;