NM_032609.3:c.-1+27C>T

Variant names:

• chr20-31637989-C-T
• rs6088855
• NM_032609.3:c.-1+27C>T

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+27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,102 control chromosomes in the GnomAD database, including 7,997 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7997 hom., cov: 32)
  • Exomes 𝑓: 0.11 (0 hom.)
• Consequence: COX4I2 NM_032609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 8 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=-0.91).
• BP6: Variant 20-31637989-C-T is Benign according to our data. Variant chr20-31637989-C-T is described in ClinVar as Benign. ClinVar VariationId is 1225894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 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+27C>T		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+27C>T		intron	N/A	ENSP00000365243.3	Q96KJ9
	COX4I2	ENST00000948152.1		c.-1+27C>T		intron	N/A	ENSP00000618211.1
	COX4I2	ENST00000890502.1		c.-1+27C>T		intron	N/A	ENSP00000560561.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43324 AN: 151956 Hom.: 7999 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0659

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.107 AC: 3 AN: 28 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 3 AN XY: 24

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.0769 AC: 2 AN: 26

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.285 AC: 43347 AN: 152074 Hom.: 7997 Cov.: 32 AF XY: 0.282 AC XY: 20944 AN XY: 74346

African (AFR) AF: 0.519 AC: 21515 AN: 41480

American (AMR) AF: 0.204 AC: 3125 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 825 AN: 3468

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.0656 AC: 317 AN: 4834

European-Finnish (FIN) AF: 0.274 AC: 2901 AN: 10604

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.206 AC: 13992 AN: 67926

Other (OTH) AF: 0.248 AC: 525 AN: 2114

Alfa AF: 0.261 Hom.: 758

Bravo AF: 0.294

Asia WGS AF: 0.0630 AC: 220 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	-0.91
CADD	Benign	0.65
DANN	Benign	0.86
PhyloP100		-1.2
PromoterAI		0.026	Neutral
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: rs6088855; hg19: chr20-30225792;