NM_000261.2:c.1442C>G

Variant names:

• chr1-171635998-G-C
• rs2102944466
• NM_000261.2:c.1442C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PM2_Supporting PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1442C>G variant in MYOC is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 481 (p.Pro481Arg). 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. The REVEL score = 0.853, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no 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:12789574), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1442C>T, p.Pro481Leu, Grantham score = 98, PMID:10196380) in the same codon has been classified as likely pathogenic for juvenile open angle glaucoma by the ClinGen Glaucoma VCEP. The c.1442C>G, p.Pro481Arg variant has a higher Grantham score (= 103) than the previously classified amino acid change, was not predicted to affect splicing as assessed with SpliceAI (≤ 0.2), and met PP3, meeting the conditions for PM5_Supporting to apply. In summary, this variant met the criteria to receive a score of 3 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): PP3, PM2_Supporting, PM5_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA343723138/MONDO:0007665/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 5.45
• Publications: 1 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 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1442C>G	p.Pro481Arg	missense	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.1442C>G	p.Pro481Arg	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1547C>G	p.Pro516Arg	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1508C>G	p.Pro503Arg	missense	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	-	Glaucoma 1, open angle, E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.4
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.63
MutPred		0.98		Gain of MoRF binding (P = 0.0463)
MVP		1.0
MPC		0.73
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.95
Mutation Taster		=28/72	disease causing

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: rs2102944466; hg19: chr1-171605138;