rs71429371

Positions:

• chr2-97648092-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000258424.3(COX5B):​c.374A>G​(p.Gln125Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,606,336 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: COX5B ENST00000258424.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.02

Genes affected

COX5B (HGNC:2269): (cytochrome c oxidase subunit 5B) Cytochrome C oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer and proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Vb of the human mitochondrial respiratory chain enzyme. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01726377).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX5B	NM_001862.3	c.374A>G	p.Gln125Arg	missense_variant	4/4	ENST00000258424.3	NP_001853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX5B	ENST00000258424.3	c.374A>G	p.Gln125Arg	missense_variant	4/4	1	NM_001862.3	ENSP00000258424	P1
COX5B	ENST00000464949.5	n.514A>G		non_coding_transcript_exon_variant	5/5	5
COX5B	ENST00000491989.1	n.524A>G		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152240 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000304 AC: 74 AN: 243114 Hom.: 0 AF XY: 0.000266 AC XY: 35 AN XY: 131728

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000315

Gnomad ASJ exome AF: 0.00316

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000691

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000235 AC: 342 AN: 1453978 Hom.: 2 Cov.: 30 AF XY: 0.000217 AC XY: 157 AN XY: 723052

Gnomad4 AFR exome AF: 0.0000911

Gnomad4 AMR exome AF: 0.000212

Gnomad4 ASJ exome AF: 0.00351

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74510

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000436

EpiControl AF: 0.000357

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.0097
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.13
Sift	Benign	0.033	D
Sift4G	Uncertain	0.057	T
Polyphen		0.074	B
Vest4		0.12
MVP		0.39
MPC		0.42
ClinPred		0.059	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.43

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

Other links and lift over

dbSNP: rs71429371; hg19: chr2-98264555;