chr1-171635993-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_SupportingPM4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1447G>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Methionine at amino acid 483. This variant is predicted to cause a deletion of < 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:10196380), 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/CA343723116/MONDO:0007665/019

Frequency

Genomes: not found (cov: 32)

Consequence

MYOC
NM_000261.2 stop_gained

Scores

4
1
2

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 3.33
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
PM4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYOCNM_000261.2 linkuse as main transcriptc.1447G>T p.Glu483Ter stop_gained 3/3 ENST00000037502.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYOCENST00000037502.11 linkuse as main transcriptc.1447G>T p.Glu483Ter stop_gained 3/31 NM_000261.2 P1
MYOCOSENST00000637303.1 linkuse as main transcriptc.235-2637C>A intron_variant 5 A2
MYOCENST00000638471.1 linkuse as main transcriptc.*785G>T 3_prime_UTR_variant, NMD_transcript_variant 4/45

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Open-angle glaucoma Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Glaucoma Variant Curation Expert PanelApr 03, 2023The c.1447G>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Methionine at amino acid 483. This variant is predicted to cause a deletion of < 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: 10196380), 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Benign
0.45
N
MutationTaster
Benign
1.0
D
Vest4
0.83
GERP RS
3.9

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-171605133; API