19-7522767-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020533.3(MCOLN1):c.17G>T(p.Gly6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000795 in 1,257,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Publications

0 publications found

Variant links:

Genes affected

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

MCOLN1 Gene-Disease associations (from GenCC):

mucolipidosis type IV
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Lisch epithelial corneal dystrophy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MCOLN1 links:

ENSG00000305089 (HGNC:):

ENSG00000305089 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31898153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN1	NM_020533.3 link	c.17G>T	p.Gly6Val	missense_variant	Exon 1 of 14	ENST00000264079.11	NP_065394.1	Q9GZU1
LOC105372261	XR_936293.3 link	n.936+75C>A		intron_variant	Intron 2 of 2
LOC105372261	XR_936294.3 link	n.936+75C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11 link	c.17G>T	p.Gly6Val	missense_variant	Exon 1 of 14	1	NM_020533.3	ENSP00000264079.5		Q9GZU1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.95e-7

AC:

AN:

1257648

Hom.:

Cov.:

AF XY:

0.00000163

AC XY:

AN XY:

613254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25516

American (AMR)

AF:

0.00

AC:

AN:

18914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20138

East Asian (EAS)

AF:

0.00

AC:

AN:

28072

South Asian (SAS)

AF:

0.00

AC:

AN:

61330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3806

European-Non Finnish (NFE)

AF:

9.82e-7

AC:

AN:

1017962

Other (OTH)

AF:

0.00

AC:

AN:

52186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 22, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.57

T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.0

N;.

PhyloP100

2.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.66

N;.

REVEL

Benign

0.25

Sift

Uncertain

0.028

D;.

Sift4G

Uncertain

0.013

D;D

Polyphen

0.59

P;.

Vest4

0.19

MutPred

0.31

Loss of methylation at R8 (P = 0.1464);Loss of methylation at R8 (P = 0.1464);

MVP

0.81

MPC

0.53

ClinPred

0.39

GERP RS

3.8

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.18

gMVP

0.35

Mutation Taster

=93/7

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over