rs2234926

Variant names:

• chr1-171652385-C-T
• rs2234926
• NM_000261.2:c.227G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.227G>A variant in MYOC is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 76 (p.Arg76Lys). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.3468, which met the ≥ 0.01 threshold set for BA1 (10,613 alleles out of 30,602, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.203, 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. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Arg76Lys protein had similar solubility and secretion 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. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BS3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA200294/MONDO:0020367/019

• Frequency:
  • Genomes: 𝑓 0.11 (1253 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17310 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 2.86
• Publications: 74 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]

MYOC Gene-Disease associations (from GenCC):

• glaucoma 1, open angle, A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• juvenile open angle glaucoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• open-angle glaucoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.227G>A	p.Arg76Lys	missense	Exon 1 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.227G>A	p.Arg76Lys	missense	Exon 1 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.227G>A	p.Arg76Lys	missense	Exon 1 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.227G>A	p.Arg76Lys	missense	Exon 1 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16415 AN: 152108 Hom.: 1252 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.0758

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.147 AC: 37010 AN: 251002 AF XY: 0.160

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0817

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.141 AC: 206715 AN: 1461048 Hom.: 17310 Cov.: 33 AF XY: 0.148 AC XY: 107803 AN XY: 726668

African (AFR) AF: 0.0237 AC: 792 AN: 33462

American (AMR) AF: 0.102 AC: 4540 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3452 AN: 26128

East Asian (EAS) AF: 0.0568 AC: 2255 AN: 39676

South Asian (SAS) AF: 0.341 AC: 29426 AN: 86240

European-Finnish (FIN) AF: 0.162 AC: 8663 AN: 53412

Middle Eastern (MID) AF: 0.161 AC: 927 AN: 5768

European-Non Finnish (NFE) AF: 0.134 AC: 148375 AN: 1111322

Other (OTH) AF: 0.137 AC: 8285 AN: 60360

GnomAD4 genome AF: 0.108 AC: 16424 AN: 152226 Hom.: 1253 Cov.: 32 AF XY: 0.112 AC XY: 8337 AN XY: 74430

African (AFR) AF: 0.0258 AC: 1073 AN: 41542

American (AMR) AF: 0.102 AC: 1555 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3472

East Asian (EAS) AF: 0.0762 AC: 395 AN: 5184

South Asian (SAS) AF: 0.346 AC: 1662 AN: 4810

European-Finnish (FIN) AF: 0.169 AC: 1793 AN: 10594

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9072 AN: 68008

Other (OTH) AF: 0.112 AC: 236 AN: 2112

Alfa AF: 0.117 Hom.: 969

Bravo AF: 0.0936

TwinsUK AF: 0.131 AC: 484

ALSPAC AF: 0.125 AC: 482

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.134 AC: 1155

ExAC AF: 0.150 AC: 18209

Asia WGS AF: 0.199 AC: 693 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.139

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Glaucoma 1, open angle, A (2)
-	-	2	not specified (2)
-	-	1	Glaucoma (1)
-	-	1	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.20
Sift	Benign	0.049	D
Sift4G	Benign	0.077	T
Polyphen		0.018	B
Vest4		0.064
MPC		0.19
ClinPred		0.064	T
GERP RS		3.4
PromoterAI		0.013	Neutral
Varity_R		0.13
gMVP		0.47
Mutation Taster		=99/1	polymorphism (auto)

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: rs2234926; hg19: chr1-171621525; COSMIC: COSV50674515;