1-244835733-C-T

Variant names:

• chr1-244835733-C-T
• rs959639659
• NM_198076.6:c.19C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198076.6(COX20):​c.19C>T​(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,120,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: COX20 NM_198076.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0740

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05723375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX20	NM_198076.6	c.19C>T	p.Pro7Ser	missense_variant	Exon 1 of 4	ENST00000411948.7	NP_932342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX20	ENST00000411948.7	c.19C>T	p.Pro7Ser	missense_variant	Exon 1 of 4	1	NM_198076.6	ENSP00000406327.2
COX20	ENST00000391839.6	n.78C>T		non_coding_transcript_exon_variant	Exon 1 of 3	1
COX20	ENST00000366528.3	c.19C>T	p.Pro7Ser	missense_variant	Exon 1 of 5	2		ENSP00000355486.3
COX20	ENST00000498262.1	n.75C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000134 AC: 15 AN: 1120412 Hom.: 0 Cov.: 31 AF XY: 0.0000205 AC XY: 11 AN XY: 536698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000396

Gnomad4 NFE exome AF: 0.0000149

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 11 Uncertain:1

Jan 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.61	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.030
Sift	Benign	0.059	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.30	B;.
Vest4		0.097
MutPred		0.26		Gain of phosphorylation at P7 (P = 0.0051);Gain of phosphorylation at P7 (P = 0.0051);
MVP		0.048
MPC		0.031
ClinPred		0.19	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs959639659; hg19: chr1-244999035;