NM_000261.2:c.624C>G

Variant names:

• chr1-171638703-G-C
• rs2234927
• NM_000261.2:c.624C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

This summary comes from the ClinGen Evidence Repository: The c.624C>G variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 208 (p.Asp208Glu). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.007468, which met the ≥ 0.001 threshold set for BS1 (149 alleles out of 19,952, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.126, which met the ≤ 0.15 threshold for BP4, suggesting that the variant does not impact MYOC function. The studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. As BS1 was met, PP1 did not apply and segregations were not counted. 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 met the criteria to receive a score of -5 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244210/MONDO:0007665/019

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.342
• Publications: 23 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.624C>G	p.Asp208Glu	missense	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.624C>G	p.Asp208Glu	missense	Exon 2 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.624C>G	p.Asp208Glu	missense	Exon 2 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.690C>G	p.Asp230Glu	missense	Exon 3 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000764 AC: 192 AN: 251444 AF XY: 0.000633

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00756

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000372 AC: 544 AN: 1461826 Hom.: 6 Cov.: 33 AF XY: 0.000381 AC XY: 277 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00814 AC: 323 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00161 AC: 86 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1111964

Other (OTH) AF: 0.000248 AC: 15 AN: 60392

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000463 Hom.: 0

Bravo AF: 0.000291

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Glaucoma (1)
-	-	1	Glaucoma 1, open angle, A (1)
-	-	1	Glaucoma 1, open angle, E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.73
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.036	N
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0045	T
PhyloP100		0.34
ClinPred		0.0078	T
GERP RS		2.5
Varity_R		0.026
gMVP		0.0056
Mutation Taster		=99/1	polymorphism

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: rs2234927; hg19: chr1-171607843;