1-171636382-G-T

Variant names:

• chr1-171636382-G-T
• NM_000261.2:c.1058C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000261.2(MYOC):​c.1058C>A​(p.Thr353Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T353I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 188) in uniprot entity MYOC_HUMAN there are 58 pathogenic changes around while only 11 benign (84%) in NM_000261.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-171636382-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOC	NM_000261.2	c.1058C>A	p.Thr353Lys	missense_variant	Exon 3 of 3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.1058C>A	p.Thr353Lys	missense_variant	Exon 3 of 3	1	NM_000261.2	ENSP00000037502.5
MYOCOS	ENST00000637303.1	c.235-2248G>T		intron_variant	Intron 3 of 3	5		ENSP00000490048.1
MYOC	ENST00000638471.1	n.*396C>A		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000491206.1
MYOC	ENST00000638471.1	n.*396C>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000491206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.32
Sift	Benign	0.097	T
Sift4G	Uncertain	0.040	D
Polyphen		0.73	P
Vest4		0.29
MutPred		0.53		Gain of ubiquitination at T353 (P = 0.0276);
MVP		0.91
MPC		0.30
ClinPred		0.28	T
GERP RS		3.8
Varity_R		0.25
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-171605522;