chr1-171635973-C-CG

Variant names:

• chr1-171635973-C-CG
• NM_000261.2:c.1466_1467insC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1466_1467insC variant in MYOC is an insertion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 10 of the frameshift, or amino acid 499 (p.Trp489CysfsTer10). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID:10916185), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM2_Supporting, PM4_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA1139771053/MONDO:0007665/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

Genes affected

MYOC (HGNC:7610): (myocilin) MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma. [provided by RefSeq, Jul 2008]

MYOCOS (HGNC:53429): (myocilin opposite strand)

ACMG classification

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000261.2. 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
	MYOC	NM_000261.2	MANE Select	c.1466_1467insC	p.Trp489CysfsTer10	frameshift	Exon 3 of 3	NP_000252.1	Q99972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	ENST00000037502.11	TSL:1 MANE Select	c.1466_1467insC	p.Trp489CysfsTer10	frameshift	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1571_1572insC	p.Trp524CysfsTer10	frameshift	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1532_1533insC	p.Trp511CysfsTer10	frameshift	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

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

hg19: chr1-171605113;