rs2273584

Variant names:

• chr1-235777150-C-T
• rs2273584
• NM_000081.4:c.5373G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000081.4(LYST):​c.5373G>A​(p.Lys1791Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,612,208 control chromosomes in the GnomAD database, including 123,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13097 hom., cov: 31)
  • Exomes 𝑓: 0.38 (110677 hom.)
• Consequence: LYST NM_000081.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.621

Genes affected

LYST (HGNC:1968): (lysosomal trafficking regulator) This gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. Mutations in this gene are associated with Chediak-Higashi syndrome, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants, though the full-length nature of some of these variants has not been determined. [provided by RefSeq, Apr 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-235777150-C-T is Benign according to our data. Variant chr1-235777150-C-T is described in ClinVar as [Benign]. Clinvar id is 254927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.621 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYST	NM_000081.4	c.5373G>A	p.Lys1791Lys	synonymous_variant	Exon 17 of 53	ENST00000389793.7	NP_000072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYST	ENST00000389793.7	c.5373G>A	p.Lys1791Lys	synonymous_variant	Exon 17 of 53	5	NM_000081.4	ENSP00000374443.2

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61329 AN: 151738 Hom.: 13083 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.391

GnomAD3 exomes AF: 0.344 AC: 86280 AN: 251078 Hom.: 16445 AF XY: 0.338 AC XY: 45856 AN XY: 135712

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.0588

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.381 AC: 556878 AN: 1460352 Hom.: 110677 Cov.: 33 AF XY: 0.376 AC XY: 273142 AN XY: 726616

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.0856

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.404 AC: 61392 AN: 151856 Hom.: 13097 Cov.: 31 AF XY: 0.397 AC XY: 29477 AN XY: 74204

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.0628

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.389

Alfa AF: 0.409 Hom.: 6510

Bravo AF: 0.401

Asia WGS AF: 0.153 AC: 532 AN: 3468

EpiCase AF: 0.391

EpiControl AF: 0.399

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Chédiak-Higashi syndrome Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.2
DANN	Benign	0.56

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: rs2273584; hg19: chr1-235940450; COSMIC: COSV67705051;