rs61730976

Variant names:

• chr1-171636465-C-T
• rs61730976
• NM_000261.2:c.975G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BA1 BP4 BS3_Supporting BP7

This summary comes from the ClinGen Evidence Repository: The c.975G>A variant in MYOC is a synonymous variant (p.Thr325=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.08643, which met the ≥ 0.01 threshold set for BA1 (2,157 alleles out of 24,956 which meets 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) = 0.008 which met the ≤ 10 threshold for BP4, and the GERP score = -11.5 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. A previous study (PMID:35196929) demonstrated that the Thr325= protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), 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: BA1, BP4, BP7, BS3_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244108/MONDO:0020367/019

• Frequency:
  • Genomes: 𝑓 0.025 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (136 hom.)
• Consequence: MYOC NM_000261.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -6.90
• Publications: 15 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 -11 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.
• 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.975G>A	p.Thr325Thr	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.975G>A	p.Thr325Thr	synonymous	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1080G>A	p.Thr360Thr	synonymous	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1041G>A	p.Thr347Thr	synonymous	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3757 AN: 152094 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0850

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00665 AC: 1669 AN: 251106 AF XY: 0.00498

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000696

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00283 AC: 4136 AN: 1461824 Hom.: 136 Cov.: 31 AF XY: 0.00244 AC XY: 1775 AN XY: 727210

African (AFR) AF: 0.0864 AC: 2893 AN: 33478

American (AMR) AF: 0.00519 AC: 232 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26122

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

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86248

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

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.000489 AC: 544 AN: 1111988

Other (OTH) AF: 0.00598 AC: 361 AN: 60388

GnomAD4 genome AF: 0.0248 AC: 3770 AN: 152212 Hom.: 170 Cov.: 32 AF XY: 0.0238 AC XY: 1774 AN XY: 74416

African (AFR) AF: 0.0851 AC: 3531 AN: 41516

American (AMR) AF: 0.0107 AC: 163 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68016

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0125 Hom.: 53

Bravo AF: 0.0281

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000948

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	-0.85
CADD	Benign	0.0020
DANN	Benign	0.51
PhyloP100		-6.9
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: rs61730976; hg19: chr1-171605605;