rs145977437

Variant names:

• chr1-171635941-T-C
• rs145977437
• NM_000261.2:c.1499A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-171635941-T-C
• chr1-171635941-T-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.1499A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 500 (p.Lys500Arg). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.006331, which meets the ≥0.001 threshold set for this criterion (158 alleles out of 24,958, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.502, 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. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC 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 met the criteria to receive a score of -4 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244011/MONDO:0007665/019

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.415
• Publications: 8 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 -4 ACMG points.

• 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.1499A>G	p.Lys500Arg	missense	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.1499A>G	p.Lys500Arg	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1604A>G	p.Lys535Arg	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1565A>G	p.Lys522Arg	missense	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000462 AC: 116 AN: 251338 AF XY: 0.000294

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461858 Hom.: 2 Cov.: 31 AF XY: 0.000139 AC XY: 101 AN XY: 727238

African (AFR) AF: 0.00553 AC: 185 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.000447 AC: 27 AN: 60392

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74472

African (AFR) AF: 0.00604 AC: 251 AN: 41552

American (AMR) AF: 0.000523 AC: 8 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000823 Hom.: 1

Bravo AF: 0.00202

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	MYOC-related disorder (1)
-	-	1	not provided (1)
-	-	1	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	9.1
DANN	Benign	0.40
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.41
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.37	N
REVEL	Uncertain	0.50
Sift	Benign	0.91	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.054
MVP		0.48
MPC		0.14
ClinPred		0.0060	T
GERP RS		-4.5
Varity_R		0.071
gMVP		0.77
Mutation Taster		=89/11	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: rs145977437; hg19: chr1-171605081;