chr1-226961452-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020247.5(COQ8A):​c.67G>A​(p.Val23Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000881 in 1,613,846 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V23A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00092 ( 2 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: -0.394
Variant links:
Genes affected
COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04414758).
BP6
Variant 1-226961452-G-A is Benign according to our data. Variant chr1-226961452-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136295.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=2, Likely_benign=1}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COQ8ANM_020247.5 linkc.67G>A p.Val23Met missense_variant Exon 2 of 15 ENST00000366777.4 NP_064632.2 Q8NI60-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COQ8AENST00000366777.4 linkc.67G>A p.Val23Met missense_variant Exon 2 of 15 1 NM_020247.5 ENSP00000355739.3 Q8NI60-1
ENSG00000288674ENST00000366779.6 linkn.*4794G>A non_coding_transcript_exon_variant Exon 19 of 32 2 ENSP00000355741.2
ENSG00000288674ENST00000366779.6 linkn.*4794G>A 3_prime_UTR_variant Exon 19 of 32 2 ENSP00000355741.2

Frequencies

GnomAD3 genomes
AF:
0.000539
AC:
82
AN:
152256
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000941
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000526
AC:
132
AN:
251144
Hom.:
1
AF XY:
0.000552
AC XY:
75
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00101
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000917
AC:
1340
AN:
1461472
Hom.:
2
Cov.:
31
AF XY:
0.000897
AC XY:
652
AN XY:
727060
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.000327
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0000943
Gnomad4 NFE exome
AF:
0.00115
Gnomad4 OTH exome
AF:
0.000381
GnomAD4 genome
AF:
0.000538
AC:
82
AN:
152374
Hom.:
0
Cov.:
33
AF XY:
0.000537
AC XY:
40
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000579
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000941
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000877
Hom.:
0
Bravo
AF:
0.000570
TwinsUK
AF:
0.00189
AC:
7
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000527
AC:
64
EpiCase
AF:
0.000818
EpiControl
AF:
0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2
Feb 24, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 26, 2021
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive ataxia due to ubiquinone deficiency Uncertain:2
Nov 30, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1
Nov 15, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.67G>A (p.V23M) alteration is located in exon 2 (coding exon 1) of the COQ8A gene. This alteration results from a G to A substitution at nucleotide position 67, causing the valine (V) at amino acid position 23 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1
Feb 14, 2013
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.037
N
LIST_S2
Benign
0.72
.;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.044
T;T
MetaSVM
Benign
-0.50
T
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.67
N;N
REVEL
Benign
0.23
Sift
Uncertain
0.013
D;D
Sift4G
Uncertain
0.026
D;D
Polyphen
0.92
P;P
Vest4
0.26
MVP
0.73
MPC
0.049
ClinPred
0.022
T
GERP RS
-1.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.084
gMVP
0.24

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35582308; hg19: chr1-227149153; API