14-70326416-T-C

Variant names:

• chr14-70326416-T-C
• rs1886077590
• NM_016468.7:c.238A>G

Variant summary

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

The NM_016468.7(COX16):​c.238A>G​(p.Asn80Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000347 in 1,441,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: COX16 NM_016468.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12
• Publications: 0 publications found

Genes affected

COX16 (HGNC:20213): (cytochrome c oxidase assembly factor COX16) Involved in mitochondrial cytochrome c oxidase assembly. Is integral component of mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

SYNJ2BP-COX16 (HGNC:48350): (SYNJ2BP-COX16 readthrough) This locus represents naturally occurring read-through transcription between the neighboring SYNJ2BP (synaptojanin 2 binding protein) and COX16 (COX16 cytochrome c oxidase assembly homolog (S. cerevisiae)) genes on chromosome 14. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. Alternate splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Feb 2011]

ENSG00000259033 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016468.7. 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
	COX16	NM_016468.7	MANE Select	c.238A>G	p.Asn80Asp	missense	Exon 4 of 4	NP_057552.1	Q9P0S2
	SYNJ2BP-COX16	NM_001202547.2		c.493A>G	p.Asn165Asp	missense	Exon 6 of 6	NP_001189476.1
	SYNJ2BP-COX16	NM_001202548.2		c.466A>G	p.Asn156Asp	missense	Exon 6 of 6	NP_001189477.1	A0A087WYV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX16	ENST00000389912.7	TSL:1 MANE Select	c.238A>G	p.Asn80Asp	missense	Exon 4 of 4	ENSP00000374562.5	Q9P0S2
	SYNJ2BP-COX16	ENST00000621525.4	TSL:2	c.466A>G	p.Asn156Asp	missense	Exon 6 of 6	ENSP00000482133.1	A0A087WYV9
	SYNJ2BP-COX16	ENST00000617124.4	TSL:2	c.394A>G	p.Asn132Asp	missense	Exon 5 of 5	ENSP00000484161.1	A0A087X1F5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1441494 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 716714

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

African (AFR) AF: 0.00 AC: 0 AN: 32196

American (AMR) AF: 0.00 AC: 0 AN: 41556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 39040

South Asian (SAS) AF: 0.00 AC: 0 AN: 82042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103408

Other (OTH) AF: 0.00 AC: 0 AN: 59360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00399754), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.1
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.28
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.33		Loss of MoRF binding (P = 0.082)
MVP		0.48
MPC		0.74
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.55
gMVP		0.56
Mutation Taster		=70/30	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: rs1886077590; hg19: chr14-70793133;