19-7522767-G-T

Variant names:

• chr19-7522767-G-T
• rs2146019192
• NM_020533.3:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

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: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• Lisch epithelial corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000305089 (HGNC:):

ACMG classification

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020533.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	NM_020533.3	MANE Select	c.17G>T	p.Gly6Val	missense	Exon 1 of 14	NP_065394.1	Q9GZU1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	ENST00000264079.11	TSL:1 MANE Select	c.17G>T	p.Gly6Val	missense	Exon 1 of 14	ENSP00000264079.5	Q9GZU1
	MCOLN1	ENST00000596390.1	TSL:1	n.133G>T		non_coding_transcript_exon	Exon 1 of 2
	MCOLN1	ENST00000852002.1		c.17G>T	p.Gly6Val	missense	Exon 1 of 14	ENSP00000522061.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.95e-7 AC: 1 AN: 1257648 Hom.: 0 Cov.: 30 AF XY: 0.00000163 AC XY: 1 AN XY: 613254

African (AFR) AF: 0.00 AC: 0 AN: 25516

American (AMR) AF: 0.00 AC: 0 AN: 18914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20138

East Asian (EAS) AF: 0.00 AC: 0 AN: 28072

South Asian (SAS) AF: 0.00 AC: 0 AN: 61330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3806

European-Non Finnish (NFE) AF: 9.82e-7 AC: 1 AN: 1017962

Other (OTH) AF: 0.00 AC: 0 AN: 52186

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.25
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.013	D
Polyphen		0.59	P
Vest4		0.19
MutPred		0.31		Loss of methylation at R8 (P = 0.1464)
MVP		0.81
MPC		0.53
ClinPred		0.39	T
GERP RS		3.8
PromoterAI		-0.012	Neutral
Varity_R		0.18
gMVP		0.35
Mutation Taster		=93/7	polymorphism

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: rs2146019192; hg19: chr19-7587653;