rs56314834

chr1-171636247-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000261.2(MYOC):c.1193A>G(p.Lys398Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,614,158 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• 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:7
• Conservation: PhyloP100: 0.538

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

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a disulfide_bond (size 188) in uniprot entity MYOC_HUMAN there are 57 pathogenic changes around while only 11 benign (84%) in NM_000261.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.014392197).
• BP6: Variant 1-171636247-T-C is Benign according to our data. Variant chr1-171636247-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 403218.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-171636247-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00396 (603/152266) while in subpopulation NFE AF= 0.0067 (456/68012). AF 95% confidence interval is 0.0062. There are 6 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOC	NM_000261.2	c.1193A>G	p.Lys398Arg	missense_variant	3/3	ENST00000037502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOC	ENST00000037502.11	c.1193A>G	p.Lys398Arg	missense_variant	3/3	1	NM_000261.2	P1
MYOCOS	ENST00000637303.1	c.235-2383T>C		intron_variant		5		A2
MYOC	ENST00000638471.1	c.*531A>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

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

GnomAD3 exomes AF: 0.00348 AC: 874 AN: 251440 Hom.: 1 AF XY: 0.00338 AC XY: 460 AN XY: 135896

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 SAS 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

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00744

Gnomad4 OTH exome AF: 0.00546

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

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00670

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00531 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

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	This variant is associated with the following publications: (PMID: 11152659, 17893664, 16936947, 20668460, 16431959, 17615537, 16358725, 11004290, 20981092, 22995991, 16466712) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

Glaucoma 1, open angle, A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

Glaucoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

MYOC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Glaucoma of childhood Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

May 09, 2022

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. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.93	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs56314834; hg19: chr1-171605387; COSMIC: COSV99078735;