chr19-7528703-C-T

Variant names:

• chr19-7528703-C-T
• rs612862
• NM_020533.3:c.984C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020533.3(MCOLN1):​c.984C>T​(p.Asn328Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,613,998 control chromosomes in the GnomAD database, including 79,402 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6634 hom., cov: 34)
  • Exomes 𝑓: 0.31 (72768 hom.)
• Consequence: MCOLN1 NM_020533.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006245
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.10
• Publications: 26 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: 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-7528703-C-T is Benign according to our data. Variant chr19-7528703-C-T is described in ClinVar as Benign. ClinVar VariationId is 261324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

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.984C>T	p.Asn328Asn	splice_region synonymous	Exon 8 of 14	NP_065394.1	Q9GZU1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	ENST00000264079.11	TSL:1 MANE Select	c.984C>T	p.Asn328Asn	splice_region synonymous	Exon 8 of 14	ENSP00000264079.5	Q9GZU1
	MCOLN1	ENST00000852002.1		c.1152C>T	p.Asn384Asn	splice_region synonymous	Exon 8 of 14	ENSP00000522061.1
	MCOLN1	ENST00000915843.1		c.984C>T	p.Asn328Asn	splice_region synonymous	Exon 8 of 15	ENSP00000585902.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43718 AN: 152110 Hom.: 6643 Cov.: 34

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.284 AC: 71289 AN: 251070 AF XY: 0.292

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.311 AC: 454662 AN: 1461768 Hom.: 72768 Cov.: 61 AF XY: 0.312 AC XY: 226952 AN XY: 727186

African (AFR) AF: 0.232 AC: 7769 AN: 33478

American (AMR) AF: 0.181 AC: 8101 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10536 AN: 26136

East Asian (EAS) AF: 0.138 AC: 5475 AN: 39700

South Asian (SAS) AF: 0.283 AC: 24408 AN: 86258

European-Finnish (FIN) AF: 0.279 AC: 14911 AN: 53376

Middle Eastern (MID) AF: 0.445 AC: 2565 AN: 5768

European-Non Finnish (NFE) AF: 0.326 AC: 361938 AN: 1111936

Other (OTH) AF: 0.314 AC: 18959 AN: 60396

GnomAD4 genome AF: 0.287 AC: 43713 AN: 152230 Hom.: 6634 Cov.: 34 AF XY: 0.285 AC XY: 21207 AN XY: 74426

African (AFR) AF: 0.240 AC: 9970 AN: 41542

American (AMR) AF: 0.253 AC: 3868 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1433 AN: 3464

East Asian (EAS) AF: 0.150 AC: 775 AN: 5176

South Asian (SAS) AF: 0.276 AC: 1331 AN: 4826

European-Finnish (FIN) AF: 0.274 AC: 2904 AN: 10602

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22495 AN: 67998

Other (OTH) AF: 0.321 AC: 679 AN: 2116

Alfa AF: 0.319 Hom.: 32355

Bravo AF: 0.282

Asia WGS AF: 0.236 AC: 822 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.351

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Mucolipidosis type IV (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.35
DANN	Benign	0.84
PhyloP100		-2.1
PromoterAI		-0.031	Neutral
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs612862; hg19: chr19-7593589; COSMIC: COSV51175329; COSMIC: COSV51175329;