20-31639964-C-T

Variant names:

• chr20-31639964-C-T
• rs61759491
• NM_032609.3:c.114C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_032609.3(COX4I2):​c.114C>T​(p.Thr38Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,996 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: COX4I2 NM_032609.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.211
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-31639964-C-T is Benign according to our data. Variant chr20-31639964-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 506588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.211 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.114C>T	p.Thr38Thr	synonymous	Exon 3 of 5	NP_115998.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX4I2	ENST00000376075.4	TSL:1 MANE Select	c.114C>T	p.Thr38Thr	synonymous	Exon 3 of 5	ENSP00000365243.3	Q96KJ9
	COX4I2	ENST00000948152.1		c.114C>T	p.Thr38Thr	synonymous	Exon 3 of 6	ENSP00000618211.1
	COX4I2	ENST00000890502.1		c.108C>T	p.Thr36Thr	synonymous	Exon 3 of 5	ENSP00000560561.1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000633 AC: 159 AN: 251264 AF XY: 0.000692

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00131 AC: 1913 AN: 1461850 Hom.: 4 Cov.: 32 AF XY: 0.00128 AC XY: 934 AN XY: 727218

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00164 AC: 1824 AN: 1112004

Other (OTH) AF: 0.000861 AC: 52 AN: 60392

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152146 Hom.: 0 Cov.: 31 AF XY: 0.000646 AC XY: 48 AN XY: 74310

African (AFR) AF: 0.000458 AC: 19 AN: 41444

American (AMR) AF: 0.000262 AC: 4 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000646

EpiCase AF: 0.00115

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	COX4I2-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.32
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61759491; hg19: chr20-30227767;