rs6425363

Variant names:

• chr1-171648253-C-T
• rs6425363
• NM_000261.2:c.604+3755G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000261.2(MYOC):​c.604+3755G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 151,890 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.094 (685 hom., cov: 31)
• Consequence: MYOC NM_000261.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.402
• Publications: 1 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]

MYOC Gene-Disease associations (from GenCC):

• glaucoma 1, open angle, A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• juvenile open angle glaucoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• open-angle glaucoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOC	NM_000261.2	c.604+3755G>A		intron_variant	Intron 1 of 2	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.604+3755G>A		intron_variant	Intron 1 of 2	1	NM_000261.2	ENSP00000037502.5
MYOC	ENST00000638471.1	n.130+4229G>A		intron_variant	Intron 1 of 3	5		ENSP00000491206.1

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14248 AN: 151778 Hom.: 681 Cov.: 31

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.0879

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0912

Gnomad OTH AF: 0.0874

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0939 AC: 14261 AN: 151890 Hom.: 685 Cov.: 31 AF XY: 0.0960 AC XY: 7127 AN XY: 74228

African (AFR) AF: 0.0764 AC: 3165 AN: 41414

American (AMR) AF: 0.102 AC: 1558 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1084 AN: 5164

South Asian (SAS) AF: 0.0880 AC: 424 AN: 4818

European-Finnish (FIN) AF: 0.113 AC: 1183 AN: 10514

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0912 AC: 6197 AN: 67964

Other (OTH) AF: 0.0932 AC: 196 AN: 2104

Alfa AF: 0.0882 Hom.: 89

Bravo AF: 0.0935

Asia WGS AF: 0.197 AC: 685 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.76
DANN	Benign	0.55
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs6425363; hg19: chr1-171617393; COSMIC: COSV50674388;