Genetic Variant MCOLN1:c.31+10C>T (chr19-7522791-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_020533.3(MCOLN1):c.31+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000846 in 1,182,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.898

Publications

0 publications found

Variant links:

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

MCOLN1 links:

ENSG00000305089 (HGNC:):

ENSG00000305089 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-7522791-C-T is Benign according to our data. Variant chr19-7522791-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2061828.Status of the report is criteria_provided_single_submitter, 1 stars.

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.31+10C>T		intron	N/A	NP_065394.1	Q9GZU1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MCOLN1	ENST00000264079.11	TSL:1 MANE Select	c.31+10C>T	intron	N/A	ENSP00000264079.5	Q9GZU1
MCOLN1	ENST00000596390.1	TSL:1	n.147+10C>T	intron	N/A
MCOLN1	ENST00000852002.1		c.31+10C>T	intron	N/A	ENSP00000522061.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.46e-7

AC:

AN:

1182346

Hom.:

Cov.:

AF XY:

0.00000175

AC XY:

AN XY:

570616

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23668

American (AMR)

AF:

0.00

AC:

AN:

9622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16468

East Asian (EAS)

AF:

0.00

AC:

AN:

27106

South Asian (SAS)

AF:

0.00

AC:

AN:

46938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3590

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

979918

Other (OTH)

AF:

0.00

AC:

AN:

48536

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucolipidosis type IV (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.90

PromoterAI

0.0086

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over