20-31639964-C-T

Position:

• chr20-31639964-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_032609.3(COX4I2):​c.114C>T​(p.Thr38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,996 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: COX4I2 NM_032609.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.211

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-31639964-C-T is Benign according to our data. Variant chr20-31639964-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 506588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.211 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I2	NM_032609.3	c.114C>T	p.Thr38=	synonymous_variant	3/5	ENST00000376075.4	NP_115998.2
COX4I2	XM_005260579.5	c.129C>T	p.Thr43=	synonymous_variant	2/4		XP_005260636.1
COX4I2	XM_005260580.5	c.129C>T	p.Thr43=	synonymous_variant	2/3		XP_005260637.1
COX4I2	XM_005260581.4	c.114C>T	p.Thr38=	synonymous_variant	3/4		XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4	c.114C>T	p.Thr38=	synonymous_variant	3/5	1	NM_032609.3	ENSP00000365243	P1
COX4I2	ENST00000490030.1	n.144C>T		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000633 AC: 159 AN: 251264 Hom.: 1 AF XY: 0.000692 AC XY: 94 AN XY: 135798

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00131 AC: 1913 AN: 1461850 Hom.: 4 Cov.: 32 AF XY: 0.00128 AC XY: 934 AN XY: 727218

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152146 Hom.: 0 Cov.: 31 AF XY: 0.000646 AC XY: 48 AN XY: 74310

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000646

EpiCase AF: 0.00115

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2017

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. -

COX4I2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61759491; hg19: chr20-30227767;