rs56314834

Variant names:

• chr1-171636247-T-C
• rs56314834
• NM_000261.2:c.1193A>G

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.1193A>G variant in MYOC is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 398 (p.Lys398Arg). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.005978, which met the ≥ 0.001 threshold set for BS1 (772 alleles out of 129,138, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.207, 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 (PMID:16466712, 10545602, 11004290) demonstrated that the Lys398Arg 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/CA1244064/MONDO:0020367/019

• Frequency:
  • Genomes: 𝑓 0.0040 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (32 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 0.538
• 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.

• 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.1193A>G	p.Lys398Arg	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.1193A>G	p.Lys398Arg	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1298A>G	p.Lys433Arg	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1259A>G	p.Lys420Arg	missense	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 603 AN: 152148 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00348 AC: 874 AN: 251440 AF XY: 0.00338

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00606 AC: 8853 AN: 1461892 Hom.: 32 Cov.: 31 AF XY: 0.00582 AC XY: 4234 AN XY: 727248

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00414 AC: 185 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00744 AC: 8276 AN: 1112012

Other (OTH) AF: 0.00546 AC: 330 AN: 60394

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152266 Hom.: 6 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74444

African (AFR) AF: 0.00142 AC: 59 AN: 41552

American (AMR) AF: 0.00458 AC: 70 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00670 AC: 456 AN: 68012

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00506 Hom.: 1

Bravo AF: 0.00428

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00317 AC: 385

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Glaucoma (1)
-	-	1	Glaucoma 1, open angle, A (1)
-	-	1	Glaucoma of childhood (1)
-	-	1	MYOC-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.54
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.21
Sift	Benign	0.62	T
Sift4G	Benign	0.41	T
Polyphen		0.10	B
Vest4		0.068
MVP		0.80
MPC		0.17
ClinPred		0.0077	T
GERP RS		-1.2
Varity_R		0.16
gMVP		0.65
Mutation Taster		=96/4	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: rs56314834; hg19: chr1-171605387; COSMIC: COSV99078735;