20-31639012-C-T

Variant names:

• chr20-31639012-C-T
• rs201853480
• NM_032609.3:c.1-6C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId is 338031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1-6C>T		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.1-6C>T		splice_region intron	N/A	ENSP00000365243.3	Q96KJ9
	COX4I2	ENST00000948152.1		c.1-6C>T		splice_region intron	N/A	ENSP00000618211.1
	COX4I2	ENST00000890502.1		c.1-6C>T		splice_region intron	N/A	ENSP00000560561.1

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

GnomAD2 exomes AF: 0.00131 AC: 316 AN: 241284 AF XY: 0.00156

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 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

African (AFR) AF: 0.0000897 AC: 3 AN: 33448

American (AMR) AF: 0.000980 AC: 43 AN: 43862

Ashkenazi Jewish (ASJ) AF: 0.00205 AC: 53 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00444 AC: 376 AN: 84632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.0152 AC: 87 AN: 5742

European-Non Finnish (NFE) AF: 0.000629 AC: 698 AN: 1109698

Other (OTH) AF: 0.00133 AC: 80 AN: 60206

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

African (AFR) AF: 0.0000963 AC: 4 AN: 41554

American (AMR) AF: 0.000785 AC: 12 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000991 Hom.: 1

Bravo AF: 0.000790

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.0
DANN	Benign	0.46
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201853480; hg19: chr20-30226815;