rs61736600

Positions:

• chr19-7528685-A-C
• chr19-7528685-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020533.3(MCOLN1):​c.966A>C​(p.Arg322=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0709 in 1,613,996 control chromosomes in the GnomAD database, including 4,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R322R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.059 (320 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4280 hom.)
• Consequence: MCOLN1 NM_020533.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.37

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-7528685-A-C is Benign according to our data. Variant chr19-7528685-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 261323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCOLN1	NM_020533.3	c.966A>C	p.Arg322=	synonymous_variant	8/14	ENST00000264079.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCOLN1	ENST00000264079.11	c.966A>C	p.Arg322=	synonymous_variant	8/14	1	NM_020533.3	P1
MCOLN1	ENST00000394321.9	n.1281A>C		non_coding_transcript_exon_variant	7/13	2
MCOLN1	ENST00000595860.5	n.32A>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8988 AN: 152052 Hom.: 318 Cov.: 33

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0654

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0796

Gnomad OTH AF: 0.0698

GnomAD3 exomes AF: 0.0561 AC: 14099 AN: 251278 Hom.: 519 AF XY: 0.0570 AC XY: 7746 AN XY: 135824

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.0461

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0797

Gnomad OTH exome AF: 0.0699

GnomAD4 exome AF: 0.0722 AC: 105513 AN: 1461826 Hom.: 4280 Cov.: 34 AF XY: 0.0710 AC XY: 51627 AN XY: 727218

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.0469

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.0395

Gnomad4 NFE exome AF: 0.0816

Gnomad4 OTH exome AF: 0.0689

GnomAD4 genome AF: 0.0591 AC: 8990 AN: 152170 Hom.: 320 Cov.: 33 AF XY: 0.0563 AC XY: 4187 AN XY: 74382

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.0652

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.0345

Gnomad4 NFE AF: 0.0796

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.0588 Hom.: 148

Bravo AF: 0.0611

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0824

EpiControl AF: 0.0885

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucolipidosis type IV Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.091
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs61736600; hg19: chr19-7593571;