NM_000261.2:c.612G>T

Variant names:

• chr1-171638715-C-A
• rs57824969
• NM_000261.2:c.612G>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.612G>T variant in MYOC is a synonymous variant (p.Thr204=). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.01075, which met the ≥ 0.01 threshold set for BA1 (268 alleles out of 24,932, 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) = 0.126 which met the ≤ 10 threshold for BP4, and the GERP score = -5.55 (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 Thr204= 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. Although probands with 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 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, BS3_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244212/MONDO:0007665/019

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: MYOC NM_000261.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.800
• Publications: 5 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

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.612G>T	p.Thr204Thr	synonymous	Exon 2 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.612G>T	p.Thr204Thr	synonymous	Exon 2 of 3	ENSP00000037502.5	Q99972
	MYOCOS	ENST00000637303.1	TSL:5	c.320C>A	p.Thr107Lys	missense	Exon 4 of 4	ENSP00000490048.1	A0AAA9Y3V5
	MYOC	ENST00000971579.1		c.612G>T	p.Thr204Thr	synonymous	Exon 2 of 3	ENSP00000641638.1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152128 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000847 AC: 213 AN: 251384 AF XY: 0.000684

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000321 AC: 469 AN: 1461780 Hom.: 0 Cov.: 33 AF XY: 0.000312 AC XY: 227 AN XY: 727220

African (AFR) AF: 0.0118 AC: 394 AN: 33472

American (AMR) AF: 0.000626 AC: 28 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111942

Other (OTH) AF: 0.000530 AC: 32 AN: 60390

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152246 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74446

African (AFR) AF: 0.00980 AC: 407 AN: 41536

American (AMR) AF: 0.00111 AC: 17 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00100 Hom.: 2

Bravo AF: 0.00315

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000577 AC: 2 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	Glaucoma 1, open angle, A (2)
-	-	2	not provided (2)
-	-	1	Glaucoma (1)
-	-	1	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.2
DANN	Benign	0.43
FATHMM_MKL	Benign	0.036	N
MetaRNN	Benign	0.0034	T
PhyloP100		-0.80
GERP RS		-5.5
gMVP		0.011
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs57824969; hg19: chr1-171607855;