19-7522757-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020533.3(MCOLN1):c.11dup(p.Ala5GlyfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCOLN1 NM_020533.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.250

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]

LOC105372261 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 57 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-7522757-G-GC is Pathogenic according to our data. Variant chr19-7522757-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1726094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCOLN1	NM_020533.3	c.11dup	p.Ala5GlyfsTer83	frameshift_variant	1/14	ENST00000264079.11
LOC105372261	XR_936294.3	n.936+84_936+85insG		intron_variant, non_coding_transcript_variant
LOC105372261	XR_936293.3	n.936+84_936+85insG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCOLN1	ENST00000264079.11	c.11dup	p.Ala5GlyfsTer83	frameshift_variant	1/14	1	NM_020533.3	P1
MCOLN1	ENST00000596390.1	n.127dup		non_coding_transcript_exon_variant	1/2	1
MCOLN1	ENST00000601003.1	c.11dup	p.Ala5GlyfsTer83	frameshift_variant	1/5	3
MCOLN1	ENST00000394321.9	n.91dup		non_coding_transcript_exon_variant	1/13	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucolipidosis type IV Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 18, 2022

NM_020533.2(MCOLN1):c.11dupC(A5Gfs*83) is expected to be pathogenic in the context of mucolipidosis IV. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in MCOLN1, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

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: chr19-7587643;