Variant 1-84952244-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153259.4(MCOLN2):c.746C>T(p.Thr249Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,599,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

MCOLN2
NM_153259.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.901

Variant links:

Genes affected

MCOLN2 (HGNC:13357): (mucolipin TRP cation channel 2) Mucolipins constitute a family of cation channel proteins with homology to the transient receptor potential superfamily. In mammals, the mucolipin family includes 3 members, MCOLN1 (MIM 605248), MCOLN2, and MCOLN3 (MIM 607400), that exhibit a common 6-membrane-spanning topology. Homologs of mammalian mucolipins exist in Drosophila and C. elegans. Mutations in the human MCOLN1 gene cause mucolipodosis IV (MIM 262650) (Karacsonyi et al., 2007 [PubMed 17662026]).[supplied by OMIM, Sep 2009]

MCOLN2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054185122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN2	NM_153259.4 linkuse as main transcript	c.746C>T	p.Thr249Met	missense_variant, splice_region_variant	6/14	ENST00000370608.8	NP_694991.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN2	ENST00000370608.8 linkuse as main transcript	c.746C>T	p.Thr249Met	missense_variant, splice_region_variant	6/14	1	NM_153259.4	ENSP00000359640		Q8IZK6-1
MCOLN2	ENST00000531325.5 linkuse as main transcript	n.987C>T		splice_region_variant, non_coding_transcript_exon_variant	6/12	1
MCOLN2	ENST00000284027.5 linkuse as main transcript	c.662C>T	p.Thr221Met	missense_variant, splice_region_variant	6/14	5		ENSP00000284027	P1	Q8IZK6-2
MCOLN2	ENST00000463065.5 linkuse as main transcript	c.746C>T	p.Thr249Met	missense_variant, splice_region_variant, NMD_transcript_variant	6/12	2		ENSP00000436299

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000201

AC:

AN:

243556

Hom.:

AF XY:

0.000175

AC XY:

AN XY:

131494

show subpopulations

Gnomad AFR exome

AF:

0.000994

Gnomad AMR exome

AF:

0.0000306

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00106

Gnomad SAS exome

AF:

0.000459

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000898

AC:

130

AN:

1447750

Hom.:

Cov.:

AF XY:

0.0000860

AC XY:

AN XY:

720514

show subpopulations

Gnomad4 AFR exome

AF:

0.000946

Gnomad4 AMR exome

AF:

0.0000699

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.000707

Gnomad4 SAS exome

AF:

0.000416

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000154

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000309

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000974

Hom.:

Bravo

AF:

0.000355

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.746C>T (p.T249M) alteration is located in exon 6 (coding exon 6) of the MCOLN2 gene. This alteration results from a C to T substitution at nucleotide position 746, causing the threonine (T) at amino acid position 249 to be replaced by a methionine (M). 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

0.079

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.015

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

0.96

D;D

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.18

Sift

Benign

0.099

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.22

B;.

Vest4

0.29

MVP

0.70

MPC

0.085

ClinPred

0.045

GERP RS

-0.72

Varity_R

0.053

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over