NM_020533.3:c.29C>G

Variant names:

• chr19-7522779-C-G
• rs953773169
• NM_020533.3:c.29C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_020533.3(MCOLN1):​c.29C>G​(p.Ser10*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,216,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: MCOLN1 NM_020533.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9658
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.12
• 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: Pathogenic. The variant received 11 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 89 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.29C>G	p.Ser10*	stop_gained splice_region	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.29C>G	p.Ser10*	stop_gained splice_region	Exon 1 of 14	ENSP00000264079.5	Q9GZU1
	MCOLN1	ENST00000596390.1	TSL:1	n.145C>G		splice_region non_coding_transcript_exon	Exon 1 of 2
	MCOLN1	ENST00000852002.1		c.29C>G	p.Ser10*	stop_gained splice_region	Exon 1 of 14	ENSP00000522061.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.22e-7 AC: 1 AN: 1216242 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 590298

African (AFR) AF: 0.00 AC: 0 AN: 24310

American (AMR) AF: 0.00 AC: 0 AN: 12226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17852

East Asian (EAS) AF: 0.00 AC: 0 AN: 27556

South Asian (SAS) AF: 0.00 AC: 0 AN: 53760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3714

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 998608

Other (OTH) AF: 0.00 AC: 0 AN: 50176

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		3.1
Vest4		0.51
GERP RS		4.8
PromoterAI		0.0063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.94
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: rs953773169; hg19: chr19-7587665;