chr1-171635957-C-T

Variant names:

• chr1-171635957-C-T
• rs2102944447
• NM_000261.2:c.1483G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1483G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 495 (p.Val495Ile). 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 = 0.424, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID:10545602) demonstrated that the Val495Ile protein had similar solubility levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 proband with primary open angle glaucoma had been reported (PMID:9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 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): BS3_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343722912/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: 3.37
• 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 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.1483G>A	p.Val495Ile	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.1483G>A	p.Val495Ile	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1588G>A	p.Val530Ile	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1549G>A	p.Val517Ile	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	-	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.4
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.42
Sift	Benign	0.14	T
Sift4G	Benign	0.080	T
Polyphen		0.99	D
Vest4		0.21
MutPred		0.21		Gain of catalytic residue at V495 (P = 0.1019)
MVP		0.90
MPC		0.63
ClinPred		0.94	D
GERP RS		3.9
Varity_R		0.48
gMVP		0.66
Mutation Taster		=68/32	polymorphism

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: rs2102944447; hg19: chr1-171605097;