NM_198076.6:c.43-9dupT

Variant names:

• chr1-244841927-C-CT
• rs770522096
• NM_198076.6:c.43-9dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_198076.6(COX20):​c.43-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,459,956 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: COX20 NM_198076.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.164
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-244841927-C-CT is Benign according to our data. Variant chr1-244841927-C-CT is described in ClinVar as Benign. ClinVar VariationId is 3606802.Status of the report is criteria_provided_single_submitter, 1 stars.

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.43-9dupT		splice_region intron	N/A	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.79-9dupT		splice_region intron	N/A	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.43-9dupT		splice_region intron	N/A	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.43-9dupT		splice_region intron	N/A	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.102-260dupT		intron	N/A
	COX20	ENST00000366528.3	TSL:2	c.79-9dupT		splice_region intron	N/A	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151904 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 15 AN: 222024 AF XY: 0.0000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 136 AN: 1308052 Hom.: 0 Cov.: 21 AF XY: 0.000110 AC XY: 72 AN XY: 657420

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000347 AC: 1 AN: 28802

American (AMR) AF: 0.0000280 AC: 1 AN: 35770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23872

East Asian (EAS) AF: 0.00 AC: 0 AN: 38920

South Asian (SAS) AF: 0.000293 AC: 23 AN: 78574

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3822

European-Non Finnish (NFE) AF: 0.000107 AC: 106 AN: 990550

Other (OTH) AF: 0.0000730 AC: 4 AN: 54794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000111022), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151904 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74210

African (AFR) AF: 0.00 AC: 0 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: 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
PhyloP100		-0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs770522096; hg19: chr1-245005229; COSMIC: COSV63672964; COSMIC: COSV63672964;