19-7522766-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020533.3(MCOLN1):c.16G>T(p.Gly6Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,409,436 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: MCOLN1 NM_020533.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.512

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012184024).
• BP6: Variant 19-7522766-G-T is Benign according to our data. Variant chr19-7522766-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330485.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00249 (379/152302) while in subpopulation AFR AF= 0.0088 (366/41582). AF 95% confidence interval is 0.00806. There are 1 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCOLN1	NM_020533.3	c.16G>T	p.Gly6Cys	missense_variant	1/14	ENST00000264079.11
LOC105372261	XR_936294.3	n.936+76C>A		intron_variant, non_coding_transcript_variant
LOC105372261	XR_936293.3	n.936+76C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCOLN1	ENST00000264079.11	c.16G>T	p.Gly6Cys	missense_variant	1/14	1	NM_020533.3	P1
MCOLN1	ENST00000596390.1	n.132G>T		non_coding_transcript_exon_variant	1/2	1
MCOLN1	ENST00000601003.1	c.16G>T	p.Gly6Cys	missense_variant	1/5	3
MCOLN1	ENST00000394321.9	n.96G>T		non_coding_transcript_exon_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00880

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000223 AC: 7 AN: 31358 Hom.: 0 AF XY: 0.000109 AC XY: 2 AN XY: 18400

Gnomad AFR exome AF: 0.00772

Gnomad AMR exome AF: 0.000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 303 AN: 1257134 Hom.: 4 Cov.: 30 AF XY: 0.000215 AC XY: 132 AN XY: 612910

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.000106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000197

Gnomad4 OTH exome AF: 0.000460

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74474

Gnomad4 AFR AF: 0.00880

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00236 Hom.: 1

Bravo AF: 0.00285

ExAC AF: 0.0000630 AC: 1

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucolipidosis type IV Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	0.085
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.52	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.40	N;.
REVEL	Benign	0.24
Sift	Uncertain	0.017	D;.
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.96	D;.
Vest4		0.26
MVP		0.88
MPC		0.77
ClinPred		0.042	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs61736595; hg19: chr19-7587652;