20-31639012-C-T

Position:

• chr20-31639012-C-T

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.1-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,608,486 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00092 (6 hom.)
• Consequence: COX4I2 NM_032609.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003143
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.424

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 (BayesDel_noAF=-0.8).
• BP6: Variant 20-31639012-C-T is Benign according to our data. Variant chr20-31639012-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 338031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I2	NM_032609.3	c.1-6C>T		splice_region_variant, intron_variant		ENST00000376075.4	NP_115998.2
COX4I2	XM_005260581.4	c.1-6C>T		splice_region_variant, intron_variant			XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4	c.1-6C>T		splice_region_variant, intron_variant		1	NM_032609.3	ENSP00000365243.3
COX4I2	ENST00000490030.1	n.31-6C>T		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00131 AC: 316 AN: 241284 Hom.: 3 AF XY: 0.00156 AC XY: 203 AN XY: 130168

Gnomad AFR exome AF: 0.0000660

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00297

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00353

GnomAD4 exome AF: 0.000920 AC: 1340 AN: 1456234 Hom.: 6 Cov.: 32 AF XY: 0.00108 AC XY: 783 AN XY: 723572

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000980

Gnomad4 ASJ exome AF: 0.00205

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00444

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000629

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152252 Hom.: 0 Cov.: 31 AF XY: 0.000994 AC XY: 74 AN XY: 74438

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000991 Hom.: 1

Bravo AF: 0.000790

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COX4I2: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.0
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.070		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: rs201853480; hg19: chr20-30226815;