rs28541364

Variant names:

• chr19-7529166-C-T
• rs28541364
• NM_020533.3:c.1200C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020533.3(MCOLN1):​c.1200C>T​(p.Gly400Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,646 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (71 hom.)
• Consequence: MCOLN1 NM_020533.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.17
• Publications: 3 publications found

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: Myriad Women’s Health, ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Lisch epithelial corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 19-7529166-C-T is Benign according to our data. Variant chr19-7529166-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (2002/152286) while in subpopulation AFR AF = 0.037 (1538/41558). AF 95% confidence interval is 0.0355. There are 38 homozygotes in GnomAd4. There are 965 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	NM_020533.3	MANE Select	c.1200C>T	p.Gly400Gly	synonymous	Exon 10 of 14	NP_065394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	ENST00000264079.11	TSL:1 MANE Select	c.1200C>T	p.Gly400Gly	synonymous	Exon 10 of 14	ENSP00000264079.5
	MCOLN1	ENST00000599334.1	TSL:5	c.75C>T	p.Gly25Gly	synonymous	Exon 2 of 6	ENSP00000472176.1
	MCOLN1	ENST00000394321.9	TSL:2	n.1515C>T		non_coding_transcript_exon	Exon 9 of 13

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1998 AN: 152168 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00782 AC: 1962 AN: 251016 AF XY: 0.00594

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.0361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00238 AC: 3473 AN: 1461360 Hom.: 71 Cov.: 35 AF XY: 0.00210 AC XY: 1529 AN XY: 727024

African (AFR) AF: 0.0414 AC: 1387 AN: 33480

American (AMR) AF: 0.0359 AC: 1606 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52910

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1111996

Other (OTH) AF: 0.00391 AC: 236 AN: 60388

GnomAD4 genome AF: 0.0131 AC: 2002 AN: 152286 Hom.: 38 Cov.: 33 AF XY: 0.0130 AC XY: 965 AN XY: 74468

African (AFR) AF: 0.0370 AC: 1538 AN: 41558

American (AMR) AF: 0.0278 AC: 425 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00671 Hom.: 9

Bravo AF: 0.0168

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Mucolipidosis type IV (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		-1.2
PromoterAI		0.027	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28541364; hg19: chr19-7594052;