19-7522761-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020533.3(MCOLN1):c.11C>A(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000787 in 1,271,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: MCOLN1 NM_020533.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0390

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1708588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCOLN1	NM_020533.3	c.11C>A	p.Pro4Gln	missense_variant	1/14	ENST00000264079.11
LOC105372261	XR_936294.3	n.936+81G>T		intron_variant, non_coding_transcript_variant
LOC105372261	XR_936293.3	n.936+81G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCOLN1	ENST00000264079.11	c.11C>A	p.Pro4Gln	missense_variant	1/14	1	NM_020533.3	P1
MCOLN1	ENST00000596390.1	n.127C>A		non_coding_transcript_exon_variant	1/2	1
MCOLN1	ENST00000601003.1	c.11C>A	p.Pro4Gln	missense_variant	1/5	3
MCOLN1	ENST00000394321.9	n.91C>A		non_coding_transcript_exon_variant	1/13	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.87e-7 AC: 1 AN: 1271358 Hom.: 0 Cov.: 30 AF XY: 0.00000161 AC XY: 1 AN XY: 621094

Gnomad4 AFR exome AF: 0.0000386

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.11C>A (p.P4Q) alteration is located in exon 1 (coding exon 1) of the MCOLN1 gene. This alteration results from a C to A substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.43	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.88	D;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.64	N;.
REVEL	Benign	0.21
Sift	Uncertain	0.028	D;.
Sift4G	Benign	0.061	T;D
Polyphen		0.026	B;.
Vest4		0.21
MutPred		0.19		Gain of MoRF binding (P = 0.018);Gain of MoRF binding (P = 0.018);
MVP		0.68
MPC		0.49
ClinPred		0.21	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.55

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: rs1285448813; hg19: chr19-7587647;