rs61730977

Variant names:

• chr1-171652135-T-C
• rs61730977
• NM_000261.2:c.477A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The c.477A>G variant in MYOC is a synonymous variant (p.Leu159=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07458, which met the ≥ 0.01 threshold set for BA1 (1,860 alleles out of 24,938, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The CADD score (v1.6) = 6.353, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 4.49 (threshold <0), indicating conservation at this site. 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244271/MONDO:0020367/019

• Frequency:
  • Genomes: 𝑓 0.021 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: MYOC NM_000261.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.776
• Publications: 7 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

Specifications for MYOC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: 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.477A>G	p.Leu159Leu	synonymous	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.477A>G	p.Leu159Leu	synonymous	Exon 1 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.477A>G	p.Leu159Leu	synonymous	Exon 1 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.477A>G	p.Leu159Leu	synonymous	Exon 1 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3202 AN: 152138 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00570 AC: 1434 AN: 251448 AF XY: 0.00421

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00227 AC: 3314 AN: 1461892 Hom.: 112 Cov.: 32 AF XY: 0.00194 AC XY: 1408 AN XY: 727248

African (AFR) AF: 0.0741 AC: 2481 AN: 33480

American (AMR) AF: 0.00443 AC: 198 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

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

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.000230 AC: 256 AN: 1112012

Other (OTH) AF: 0.00512 AC: 309 AN: 60396

GnomAD4 genome AF: 0.0211 AC: 3213 AN: 152256 Hom.: 120 Cov.: 32 AF XY: 0.0202 AC XY: 1505 AN XY: 74442

African (AFR) AF: 0.0724 AC: 3008 AN: 41522

American (AMR) AF: 0.00928 AC: 142 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68008

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.00975 Hom.: 49

Bravo AF: 0.0241

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.65
PhyloP100		0.78
Mutation Taster		=100/0	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: rs61730977; hg19: chr1-171621275;