1-171635997-GG-TA

Variant names:

• chr1-171635997-GG-TA
• NM_000261.2:c.1442_1443delCCinsTA
• MYOC p.Pro481Leu

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Very_Strong PM1

The NM_000261.2(MYOC):​c.1442_1443delCCinsTA​(p.Pro481Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P481R) has been classified as Uncertain significance. The gene MYOC is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45
• 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

Specifications for MYOC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_000261.2 (MYOC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000261.2

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.1442_1443delCCinsTA	p.Pro481Leu	missense	N/A	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.1442_1443delCCinsTA	p.Pro481Leu	missense	N/A	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1547_1548delCCinsTA	p.Pro516Leu	missense	N/A	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1508_1509delCCinsTA	p.Pro503Leu	missense	N/A	ENSP00000547982.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-171605137;