1-171636302-C-T

Position:

• chr1-171636302-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PS4_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The c.1138G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 380 (p.Asp380Asn). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.842, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMID:12362081), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343724574/MONDO:0020367/019

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 7.86

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 Uncertain_significance. Variant got 3 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOC	NM_000261.2	c.1138G>A	p.Asp380Asn	missense_variant	3/3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.1138G>A	p.Asp380Asn	missense_variant	3/3	1	NM_000261.2	ENSP00000037502.5
MYOCOS	ENST00000637303.1	c.235-2328C>T		intron_variant		5		ENSP00000490048.1
MYOC	ENST00000638471.1	n.*476G>A		non_coding_transcript_exon_variant	4/4	5		ENSP00000491206.1
MYOC	ENST00000638471.1	n.*476G>A		3_prime_UTR_variant	4/4	5		ENSP00000491206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma of childhood Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 20, 2022

The c.1138G>A variant in MYOC is a missense variant predicted to cause substitution of Aspartic acid by Asparagine at amino acid 380 (p.Asp380Asn). This variant was not found in any population of gnomAD (v2.1.1), meeting the <= 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.842, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 2 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMID: 12362081), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 3 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.99		Gain of sheet (P = 0.0827);
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.96

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: rs121909194; hg19: chr1-171605442;