rs1057519347

Variant names:

• chr19-40692240-C-T
• rs1057519347
• NM_024876.4:c.1430G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_024876.4(COQ8B):​c.1430G>A​(p.Arg477Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,458,866 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R477W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: COQ8B NM_024876.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.91
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 19-40692240-C-T is Pathogenic according to our data. Variant chr19-40692240-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1430G>A	p.Arg477Gln	missense	Exon 15 of 15	NP_079152.3
	COQ8B	NM_001142555.3		c.1307G>A	p.Arg436Gln	missense	Exon 14 of 14	NP_001136027.1	Q96D53-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ8B	ENST00000324464.8	TSL:1 MANE Select	c.1430G>A	p.Arg477Gln	missense	Exon 15 of 15	ENSP00000315118.3	Q96D53-1
	COQ8B	ENST00000243583.10	TSL:1	c.1307G>A	p.Arg436Gln	missense	Exon 14 of 14	ENSP00000243583.5	Q96D53-2
	COQ8B	ENST00000871658.1		c.1475G>A	p.Arg492Gln	missense	Exon 15 of 15	ENSP00000541717.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 241932 AF XY: 0.00000761

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000928

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1458866 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725556

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1110642

Other (OTH) AF: 0.0000166 AC: 1 AN: 60208

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000415 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Nephrotic syndrome, type 9 (4)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.48	D
PhyloP100		7.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.86
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.77
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519347; hg19: chr19-41198145;