NM_000261.2:c.144G>T

Variant names:

• chr1-171652468-C-A
• rs74315339
• NM_000261.2:c.144G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS3_Supporting BS1

This summary comes from the ClinGen Evidence Repository: The c.144G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 48 (p.Gln48His). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.007937, which met the ≥ 0.001 threshold set for BS1 (243 alleles out of 30,616, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.257, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Gln48His protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BS1 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 met the criteria to receive a score of - 6 and to be classified as likely benign (likely benign classification range - 2 to - 6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA119183/MONDO:0020367/019

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (11 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely benign reviewed by expert panel P:4 B:5
• Conservation: PhyloP100: -0.0120
• Publications: 40 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]

MYOC Gene-Disease associations (from GenCC):

• glaucoma 1, open angle, A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• juvenile open angle glaucoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• open-angle glaucoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.144G>T	p.Gln48His	missense	Exon 1 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.144G>T	p.Gln48His	missense	Exon 1 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.144G>T	p.Gln48His	missense	Exon 1 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.144G>T	p.Gln48His	missense	Exon 1 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000982 AC: 246 AN: 250544 AF XY: 0.00129

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000501 AC: 733 AN: 1461886 Hom.: 11 Cov.: 33 AF XY: 0.000712 AC XY: 518 AN XY: 727244

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

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

South Asian (SAS) AF: 0.00800 AC: 690 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.000613 AC: 37 AN: 60396

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000362 AC XY: 27 AN XY: 74506

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

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

Alfa AF: 0.0000269 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	2	Glaucoma 1, open angle, A (4)
1	-	1	MYOC-related disorder (2)
1	-	-	GLAUCOMA 3, PRIMARY CONGENITAL, A, DIGENIC (1)
-	-	1	Glaucoma of childhood (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.012
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.26
Sift	Benign	0.035	D
Sift4G	Uncertain	0.029	D
Polyphen		0.039	B
Vest4		0.25
MutPred		0.73		Gain of catalytic residue at Q48 (P = 0.0491)
MVP		0.74
MPC		0.17
ClinPred		0.91	D
GERP RS		0.19
PromoterAI		-0.021	Neutral
Varity_R		0.052
gMVP		0.56
Mutation Taster		=82/18	disease causing (ClinVar)

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: rs74315339; hg19: chr1-171621608; COSMIC: COSV50674652;