chr1-171636386-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1054G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 352 (p.Glu352Lys). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.01174, which met the ≥ 0.01 threshold set for BA1 (293 alleles out of 24 954, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.514, 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, 10545602) demonstrated that the Glu352Lys 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 BA1 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 was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BS3_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA1244087/MONDO:0007665/019

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 4.08

Publications

16 publications found

Variant links:

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 links:

MYOCOS (HGNC:53429): (myocilin opposite strand)

MYOCOS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOC	NM_000261.2 link	c.1054G>A	p.Glu352Lys	missense_variant	Exon 3 of 3	ENST00000037502.11	NP_000252.1	Q99972A0A0S2Z421

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYOC	ENST00000037502.11 link	c.1054G>A	p.Glu352Lys	missense_variant	Exon 3 of 3	1	NM_000261.2	ENSP00000037502.5	Q99972
MYOC	ENST00000638471.1 link	n.*392G>A		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000491206.1	A0A1W2PP09
MYOC	ENST00000638471.1 link	n.*392G>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000491206.1	A0A1W2PP09
MYOCOS	ENST00000637303.1 link	c.235-2244C>T		intron_variant	Intron 3 of 3	5		ENSP00000490048.1	A0A1B0GUC4

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.000931

AC:

234

AN:

251390

AF XY:

0.000662

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000425

AC:

622

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

272

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0136

AC:

454

AN:

33480

American (AMR)

AF:

0.000939

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

1111998

Other (OTH)

AF:

0.00103

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00378

AC:

575

AN:

152178

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

282

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0129

AC:

535

AN:

41532

American (AMR)

AF:

0.00177

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68010

Other (OTH)

AF:

0.00332

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.00426

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYOC: BS1 -

Mar 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 12, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30484747, 9804137, 16466712) -

not specified

Benign:1

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glaucoma 1, open angle, A

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Glaucoma

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Glaucoma 1, open angle, E

Benign:1

Mar 05, 2022

ClinGen Glaucoma Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.1054G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 352 (p.Glu352Lys). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.01174, which met the >= 0.01 threshold set for BA1 (293 alleles out of 24 954, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.514, 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, 10545602) demonstrated that the Glu352Lys 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 BA1 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 was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BA1, BS3_Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.14

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.86

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.8

PhyloP100

4.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.51

Sift

Benign

0.030

Sift4G

Benign

0.092

Polyphen

1.0

Vest4

0.53

MVP

0.95

MPC

0.76

ClinPred

0.024

GERP RS

4.8

Varity_R

0.47

gMVP

0.90

Mutation Taster

=20/80

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over