NM_001008212.2:c.-255C>A

Variant names:

• chr10-13100211-C-A
• rs2580915
• NM_001008212.2:c.-255C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001008212.2(OPTN):​c.-255C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000885 in 2,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: OPTN NM_001008212.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 0 publications found

Genes affected

OPTN (HGNC:17142): (optineurin) This gene encodes the coiled-coil containing protein optineurin. Optineurin may play a role in normal-tension glaucoma and adult-onset primary open angle glaucoma. Optineurin interacts with adenovirus E3-14.7K protein and may utilize tumor necrosis factor-alpha or Fas-ligand pathways to mediate apoptosis, inflammation or vasoconstriction. Optineurin may also function in cellular morphogenesis and membrane trafficking, vesicle trafficking, and transcription activation through its interactions with the RAB8, huntingtin, and transcription factor IIIA proteins. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

CCDC3 (HGNC:23813): (coiled-coil domain containing 3) Involved in negative regulation of gene expression; negative regulation of lipid metabolic process; and negative regulation of tumor necrosis factor-mediated signaling pathway. Located in endoplasmic reticulum and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000289266 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008212.2. 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
	OPTN	NM_001008212.2	MANE Select	c.-255C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001008213.1	Q96CV9-1
	OPTN	NM_001008212.2	MANE Select	c.-255C>A		5_prime_UTR	Exon 1 of 15	NP_001008213.1	Q96CV9-1
	OPTN	NM_001008211.1		c.-324C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001008212.1	Q96CV9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPTN	ENST00000378747.8	TSL:1 MANE Select	c.-255C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000368021.3	Q96CV9-1
	OPTN	ENST00000378748.7	TSL:1	c.-324C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000368022.3	Q96CV9-1
	OPTN	ENST00000378757.6	TSL:1	c.-103C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000368032.2	Q96CV9-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.000885 AC: 2 AN: 2260 Hom.: 0 Cov.: 0 AF XY: 0.000650 AC XY: 1 AN XY: 1538

⚠️ 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: 20

American (AMR) AF: 0.00 AC: 0 AN: 16

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14

East Asian (EAS) AF: 0.00 AC: 0 AN: 80

South Asian (SAS) AF: 0.00313 AC: 2 AN: 640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1420

Other (OTH) AF: 0.00 AC: 0 AN: 46

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.0
DANN	Benign	0.80
PhyloP100		0.24
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2580915; hg19: chr10-13142211;