1-84939555-T-G

Position:

• chr1-84939555-T-G

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.1108A>C​(p.Lys370Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,613,912 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 0.024 (165 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (144 hom.)
• Consequence: MCOLN2 NM_153259.4 missense, splice_region
• Scores: Splicing: ADA: 0.4633
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.67

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=0.0037180185).
• BP6: Variant 1-84939555-T-G is Benign according to our data. Variant chr1-84939555-T-G is described in ClinVar as [Benign]. Clinvar id is 775563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN2	NM_153259.4	c.1108A>C	p.Lys370Gln	missense_variant, splice_region_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.1108A>C	p.Lys370Gln	missense_variant, splice_region_variant	9/14	1	NM_153259.4	ENSP00000359640
MCOLN2	ENST00000531325.5	n.1349A>C		splice_region_variant, non_coding_transcript_exon_variant	9/12	1
MCOLN2	ENST00000284027.5	c.1024A>C	p.Lys342Gln	missense_variant, splice_region_variant	9/14	5		ENSP00000284027	P1
MCOLN2	ENST00000463065.5	c.*45-1473A>C		intron_variant, NMD_transcript_variant		2		ENSP00000436299

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3607 AN: 152150 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00630 AC: 1581 AN: 250984 Hom.: 61 AF XY: 0.00448 AC XY: 607 AN XY: 135632

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.00429

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00246 AC: 3599 AN: 1461644 Hom.: 144 Cov.: 31 AF XY: 0.00200 AC XY: 1453 AN XY: 727134

Gnomad4 AFR exome AF: 0.0876

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.00548

GnomAD4 genome AF: 0.0238 AC: 3617 AN: 152268 Hom.: 165 Cov.: 32 AF XY: 0.0226 AC XY: 1684 AN XY: 74476

Gnomad4 AFR AF: 0.0824

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00429 Hom.: 49

Bravo AF: 0.0271

ESP6500AA AF: 0.0774 AC: 341

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00768 AC: 932

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0037	T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		1.0	D;.
Vest4		0.70
MVP		0.95
MPC		0.44
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.72
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.46
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.010		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: rs6704203; hg19: chr1-85405238;