20-31639921-TTG-T

Variant names:

• chr20-31639921-TTG-T
• rs528430338
• NM_032609.3:c.83-8_83-7delGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_032609.3(COX4I2):​c.83-8_83-7delGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,613,788 control chromosomes in the GnomAD database, including 72 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (69 hom.)
• Consequence: COX4I2 NM_032609.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.18
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 20-31639921-TTG-T is Benign according to our data. Variant chr20-31639921-TTG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338032.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.83-8_83-7delGT		splice_region 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.83-11_83-10delTG		intron	N/A	ENSP00000365243.3	Q96KJ9
	COX4I2	ENST00000948152.1		c.83-11_83-10delTG		intron	N/A	ENSP00000618211.1
	COX4I2	ENST00000890502.1		c.77-11_77-10delTG		intron	N/A	ENSP00000560561.1

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 731 AN: 152082 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00774

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00478 AC: 1201 AN: 251034 AF XY: 0.00494

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00803

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00778 AC: 11377 AN: 1461588 Hom.: 69 AF XY: 0.00770 AC XY: 5600 AN XY: 727088

African (AFR) AF: 0.00182 AC: 61 AN: 33478

American (AMR) AF: 0.00226 AC: 101 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00312 AC: 269 AN: 86256

European-Finnish (FIN) AF: 0.00264 AC: 141 AN: 53346

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5750

European-Non Finnish (NFE) AF: 0.00945 AC: 10512 AN: 1111844

Other (OTH) AF: 0.00469 AC: 283 AN: 60380

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152200 Hom.: 3 Cov.: 31 AF XY: 0.00465 AC XY: 346 AN XY: 74402

African (AFR) AF: 0.00185 AC: 77 AN: 41548

American (AMR) AF: 0.00236 AC: 36 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00774 AC: 526 AN: 67990

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00569 Hom.: 0

Bravo AF: 0.00495

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Pancreatic insufficiency-anemia-hyperostosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs528430338; hg19: chr20-30227724;