rs961420748

Variant names:

• chr1-244835720-C-T
• rs961420748
• NM_198076.6:c.6C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_198076.6(COX20):​c.6C>T​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,267,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: COX20 NM_198076.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.07
• Publications: 0 publications found

Genes affected

COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

COX20 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex IV deficiency, nuclear type 11

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-244835720-C-T is Benign according to our data. Variant chr1-244835720-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1942531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198076.6. 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
	COX20	NM_198076.6	MANE Select	c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 4	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 5	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.6C>T	p.Ala2Ala	synonymous	Exon 2 of 5	NP_001299800.1	Q5RI15-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	ENST00000411948.7	TSL:1 MANE Select	c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.65C>T		non_coding_transcript_exon	Exon 1 of 3
	COX20	ENST00000366528.3	TSL:2	c.6C>T	p.Ala2Ala	synonymous	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151806 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000986 AC: 11 AN: 1115260 Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 6 AN XY: 533640

African (AFR) AF: 0.00 AC: 0 AN: 23488

American (AMR) AF: 0.0000921 AC: 1 AN: 10856

Ashkenazi Jewish (ASJ) AF: 0.0000640 AC: 1 AN: 15616

East Asian (EAS) AF: 0.00 AC: 0 AN: 26926

South Asian (SAS) AF: 0.00 AC: 0 AN: 29726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3342

European-Non Finnish (NFE) AF: 0.00000855 AC: 8 AN: 936068

Other (OTH) AF: 0.0000223 AC: 1 AN: 44886

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151806 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74134

African (AFR) AF: 0.0000242 AC: 1 AN: 41298

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.8
DANN	Benign	0.91
PhyloP100		-2.1
PromoterAI		-0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs961420748; hg19: chr1-244999022;