chr20-31639938-G-C

Position:

• chr20-31639938-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032609.3(COX4I2):​c.88G>C​(p.Gly30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,038 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: COX4I2 NM_032609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.103

Genes affected

COX4I2 (HGNC:16232): (cytochrome c oxidase subunit 4I2) Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]

COX4I2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008730233).
• BP6: Variant 20-31639938-G-C is Benign according to our data. Variant chr20-31639938-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 618043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I2	NM_032609.3	c.88G>C	p.Gly30Arg	missense_variant	3/5	ENST00000376075.4	NP_115998.2
COX4I2	XM_005260579.5	c.103G>C	p.Gly35Arg	missense_variant	2/4		XP_005260636.1
COX4I2	XM_005260580.5	c.103G>C	p.Gly35Arg	missense_variant	2/3		XP_005260637.1
COX4I2	XM_005260581.4	c.88G>C	p.Gly30Arg	missense_variant	3/4		XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4	c.88G>C	p.Gly30Arg	missense_variant	3/5	1	NM_032609.3	ENSP00000365243.3
COX4I2	ENST00000490030.1	n.118G>C		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152136 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00122 AC: 306 AN: 251172 Hom.: 0 AF XY: 0.00131 AC XY: 178 AN XY: 135776

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00129 AC: 1889 AN: 1461784 Hom.: 2 Cov.: 32 AF XY: 0.00133 AC XY: 970 AN XY: 727210

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152254 Hom.: 1 Cov.: 31 AF XY: 0.000940 AC XY: 70 AN XY: 74442

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000918

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00104

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pancreatic insufficiency-anemia-hyperostosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 08, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.74
DANN	Benign	0.79
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.053
Sift	Benign	0.036	D
Sift4G	Benign	0.076	T
Polyphen		0.0020	B
Vest4		0.27
MVP		0.37
MPC		0.15
ClinPred		0.0086	T
GERP RS		-0.73
Varity_R		0.056
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

Other links and lift over

dbSNP: rs148327783; hg19: chr20-30227741;