rs61730976

Positions:

• chr1-171636465-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP7 BA1 BP4 BS3_Supporting

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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOC	NM_000261.2	c.975G>A	p.Thr325=	synonymous_variant	3/3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.975G>A	p.Thr325=	synonymous_variant	3/3	1	NM_000261.2	ENSP00000037502	P1
MYOCOS	ENST00000637303.1	c.235-2165C>T		intron_variant		5		ENSP00000490048	A2
MYOC	ENST00000638471.1	c.*313G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5		ENSP00000491206

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

GnomAD3 exomes AF: 0.00665 AC: 1669 AN: 251106 Hom.: 70 AF XY: 0.00498 AC XY: 676 AN XY: 135696

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 SAS exome AF: 0.0000981

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

Gnomad4 AFR exome AF: 0.0864

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000489

Gnomad4 OTH exome AF: 0.00598

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

Gnomad4 AFR AF: 0.0851

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0124 Hom.: 40

Bravo AF: 0.0281

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glaucoma 1, open angle, A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glaucoma of childhood Benign:1

Benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Nov 13, 2023

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0020
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs61730976; hg19: chr1-171605605;