20-31638961-G-C

Variant names:

• chr20-31638961-G-C
• rs6088857
• NM_032609.3:c.1-57G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032609.3(COX4I2):​c.1-57G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,541,092 control chromosomes in the GnomAD database, including 38,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8278 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30204 hom.)
• Consequence: COX4I2 NM_032609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• pancreatic insufficiency-anemia-hyperostosis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-31638961-G-C is Benign according to our data. Variant chr20-31638961-G-C is described in ClinVar as Benign. ClinVar VariationId is 1244826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX4I2	NM_032609.3	MANE Select	c.1-57G>C		intron	N/A	NP_115998.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX4I2	ENST00000376075.4	TSL:1 MANE Select	c.1-57G>C		intron	N/A	ENSP00000365243.3	Q96KJ9
	COX4I2	ENST00000948152.1		c.1-57G>C		intron	N/A	ENSP00000618211.1
	COX4I2	ENST00000890502.1		c.1-57G>C		intron	N/A	ENSP00000560561.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43697 AN: 151952 Hom.: 8279 Cov.: 32

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0666

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.154

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.194 AC: 268989 AN: 1389022 Hom.: 30204 AF XY: 0.189 AC XY: 130219 AN XY: 688704

African (AFR) AF: 0.550 AC: 17650 AN: 32096

American (AMR) AF: 0.142 AC: 5302 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5613 AN: 25110

East Asian (EAS) AF: 0.000213 AC: 8 AN: 37610

South Asian (SAS) AF: 0.0677 AC: 5445 AN: 80386

European-Finnish (FIN) AF: 0.266 AC: 13384 AN: 50380

Middle Eastern (MID) AF: 0.153 AC: 863 AN: 5650

European-Non Finnish (NFE) AF: 0.197 AC: 208982 AN: 1062750

Other (OTH) AF: 0.203 AC: 11742 AN: 57752

GnomAD4 genome AF: 0.288 AC: 43723 AN: 152070 Hom.: 8278 Cov.: 32 AF XY: 0.284 AC XY: 21115 AN XY: 74314

African (AFR) AF: 0.536 AC: 22216 AN: 41474

American (AMR) AF: 0.200 AC: 3055 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0662 AC: 319 AN: 4816

European-Finnish (FIN) AF: 0.274 AC: 2894 AN: 10574

Middle Eastern (MID) AF: 0.155 AC: 45 AN: 290

European-Non Finnish (NFE) AF: 0.202 AC: 13757 AN: 67964

Other (OTH) AF: 0.250 AC: 528 AN: 2112

Alfa AF: 0.260 Hom.: 770

Bravo AF: 0.297

Asia WGS AF: 0.0640 AC: 224 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.81
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6088857; hg19: chr20-30226764;