NM_198076.6:c.61T>G

Variant names:

• chr1-244841962-T-G
• rs1680217662
• NM_198076.6:c.61T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198076.6(COX20):​c.61T>G​(p.Phe21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F21S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COX20 NM_198076.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• 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]

HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

HNRNPU Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 54

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1691927).

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.61T>G	p.Phe21Val	missense	Exon 2 of 4	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.97T>G	p.Phe33Val	missense	Exon 3 of 5	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.61T>G	p.Phe21Val	missense	Exon 3 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.61T>G	p.Phe21Val	missense	Exon 2 of 4	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.102-233T>G		intron	N/A
	COX20	ENST00000366528.3	TSL:2	c.97T>G	p.Phe33Val	missense	Exon 3 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444660 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 719544

African (AFR) AF: 0.00 AC: 0 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098306

Other (OTH) AF: 0.00 AC: 0 AN: 59664

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.097
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.050	T
Polyphen		0.036	B
Vest4		0.43
MutPred		0.34		Gain of catalytic residue at F21 (P = 0.0247)
MVP		0.088
MPC		0.036
ClinPred		0.44	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.41
Mutation Taster		=87/13	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: rs1680217662; hg19: chr1-245005264;