NM_000261.2:c.1496T>G

Variant names:

• chr1-171635944-A-C
• rs2102944438
• NM_000261.2:c.1496T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3 PM2_Supporting PS3_Supporting PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1496T>G variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Serine at amino acid 499 (p.Ile499Ser). 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 = 0.798, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID:11004290) demonstrated that the Ile499Ser protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. Only 1 segregation had been reported for juvenile open angle glaucoma (JOAG) (PMID:11004290), not meeting the ≥ 3 segregations required for PP1. Only 1 proband with JOAG had been reported (PMID:11004290), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. Another missense variant (c.1495A>T, p.Ile499Phe, Grantham score = 21, PMID:9328473) in the same codon has been classified as likely pathogenic for JOAG by the ClinGen Glaucoma VCEP. The c.1496T>G, p.Ile499Ser variant has a higher Grantham score (= 142) 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 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS3_Supporting, PM2_Supporting, PM5_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA343722837/MONDO:0020367/019

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 5.97
• 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 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1496T>G	p.Ile499Ser	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.1496T>G	p.Ile499Ser	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1601T>G	p.Ile534Ser	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1562T>G	p.Ile521Ser	missense	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Glaucoma of childhood (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.75
MutPred		0.95		Gain of disorder (P = 0.0127)
MVP		0.92
MPC		0.46
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.98
Mutation Taster		=17/83	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: rs2102944438; hg19: chr1-171605084;