1-84939570-T-C

Position:

• chr1-84939570-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153259.4(MCOLN2):​c.1093A>G​(p.Met365Val) variant causes a missense change. The variant allele was found at a frequency of 0.00509 in 1,613,904 control chromosomes in the GnomAD database, including 379 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (215 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (164 hom.)
• Consequence: MCOLN2 NM_153259.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.95

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027332306).
• BP6: Variant 1-84939570-T-C is Benign according to our data. Variant chr1-84939570-T-C is described in ClinVar as [Benign]. Clinvar id is 787751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN2	NM_153259.4	c.1093A>G	p.Met365Val	missense_variant	9/14	ENST00000370608.8	NP_694991.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN2	ENST00000370608.8	c.1093A>G	p.Met365Val	missense_variant	9/14	1	NM_153259.4	ENSP00000359640
MCOLN2	ENST00000531325.5	n.1334A>G		non_coding_transcript_exon_variant	9/12	1
MCOLN2	ENST00000284027.5	c.1009A>G	p.Met337Val	missense_variant	9/14	5		ENSP00000284027	P1
MCOLN2	ENST00000463065.5	c.*45-1488A>G		intron_variant, NMD_transcript_variant		2		ENSP00000436299

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4128 AN: 152136 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00682 AC: 1713 AN: 251004 Hom.: 83 AF XY: 0.00511 AC XY: 693 AN XY: 135660

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00279 AC: 4079 AN: 1461650 Hom.: 164 Cov.: 31 AF XY: 0.00243 AC XY: 1770 AN XY: 727126

Gnomad4 AFR exome AF: 0.0960

Gnomad4 AMR exome AF: 0.00497

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.0271 AC: 4132 AN: 152254 Hom.: 215 Cov.: 32 AF XY: 0.0257 AC XY: 1910 AN XY: 74462

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00622 Hom.: 57

Bravo AF: 0.0308

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0978 AC: 431

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00858 AC: 1042

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.0034	T;.
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.57	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.25	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.067	B;.
Vest4		0.23
MVP		0.86
MPC		0.084
ClinPred		0.016	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.82

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: rs17117841; hg19: chr1-85405253;