rs61730975

Variant names:

• chr1-171636252-C-T
• rs61730975
• NM_000261.2:c.1188G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.1188G>A variant in MYOC is a synonymous variant (p.Glu396=). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.02893, which met the ≥ 0.01 threshold set for BA1 (722 alleles out of 24,958, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.360 which met the ≤ 10 threshold for BP4, and the GERP score = -4.66 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with POAG 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BP4, BP7 LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244067/MONDO:0007665/019

• Frequency:
  • Genomes: 𝑓 0.0079 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: MYOC NM_000261.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.874
• Publications: 6 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

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.1188G>A	p.Glu396Glu	synonymous	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.1188G>A	p.Glu396Glu	synonymous	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1293G>A	p.Glu431Glu	synonymous	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1254G>A	p.Glu418Glu	synonymous	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1196 AN: 152104 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00208 AC: 523 AN: 251424 AF XY: 0.00145

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000749 AC: 1095 AN: 1461892 Hom.: 11 Cov.: 31 AF XY: 0.000660 AC XY: 480 AN XY: 727246

African (AFR) AF: 0.0274 AC: 918 AN: 33480

American (AMR) AF: 0.00114 AC: 51 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: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112010

Other (OTH) AF: 0.00167 AC: 101 AN: 60396

GnomAD4 genome AF: 0.00793 AC: 1207 AN: 152222 Hom.: 15 Cov.: 32 AF XY: 0.00730 AC XY: 543 AN XY: 74416

African (AFR) AF: 0.0277 AC: 1151 AN: 41510

American (AMR) AF: 0.00203 AC: 31 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00415 Hom.: 6

Bravo AF: 0.00892

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.78
CADD	Benign	0.17
DANN	Benign	0.62
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61730975; hg19: chr1-171605392;