chr19-40692211-C-G

Variant names:

• chr19-40692211-C-G
• rs751280402
• NM_024876.4:c.1459G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024876.4(COQ8B):​c.1459G>C​(p.Ala487Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A487S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COQ8B NM_024876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1459G>C	p.Ala487Pro	missense	Exon 15 of 15	NP_079152.3
	COQ8B	NM_001142555.3		c.1336G>C	p.Ala446Pro	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.1459G>C	p.Ala487Pro	missense	Exon 15 of 15	ENSP00000315118.3	Q96D53-1
	COQ8B	ENST00000243583.10	TSL:1	c.1336G>C	p.Ala446Pro	missense	Exon 14 of 14	ENSP00000243583.5	Q96D53-2
	COQ8B	ENST00000871658.1		c.1504G>C	p.Ala502Pro	missense	Exon 15 of 15	ENSP00000541717.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000438 AC: 1 AN: 228136 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000591

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.48	T
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.73	P
Vest4		0.65
MutPred		0.62		Gain of disorder (P = 0.0428)
MVP		0.79
MPC		0.77
ClinPred		0.62	D
GERP RS		4.3
Varity_R		0.77
gMVP		0.89
Mutation Taster		=46/54	disease causing

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: rs751280402; hg19: chr19-41198116;