1-235759143-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000081.4(LYST):​c.6710A>C​(p.Gln2237Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,614,070 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2237R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

LYST
NM_000081.4 missense

Scores

1
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 7.19
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07318425).
BP6
Variant 1-235759143-T-G is Benign according to our data. Variant chr1-235759143-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211411.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5}. Variant chr1-235759143-T-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152230) while in subpopulation NFE AF= 0.00223 (152/68022). AF 95% confidence interval is 0.00195. There are 2 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LYSTNM_000081.4 linkc.6710A>C p.Gln2237Pro missense_variant Exon 23 of 53 ENST00000389793.7 NP_000072.2 Q99698-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LYSTENST00000389793.7 linkc.6710A>C p.Gln2237Pro missense_variant Exon 23 of 53 5 NM_000081.4 ENSP00000374443.2 Q99698-1

Frequencies

GnomAD3 genomes
AF:
0.00138
AC:
210
AN:
152230
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00547
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00216
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00223
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00138
AC:
346
AN:
250670
Hom.:
1
AF XY:
0.00136
AC XY:
184
AN XY:
135438
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000261
Gnomad ASJ exome
AF:
0.00467
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00287
Gnomad NFE exome
AF:
0.00195
Gnomad OTH exome
AF:
0.000981
GnomAD4 exome
AF:
0.00132
AC:
1926
AN:
1461840
Hom.:
4
Cov.:
33
AF XY:
0.00133
AC XY:
970
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00379
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00275
Gnomad4 NFE exome
AF:
0.00142
Gnomad4 OTH exome
AF:
0.00132
GnomAD4 genome
AF:
0.00138
AC:
210
AN:
152230
Hom.:
2
Cov.:
32
AF XY:
0.00144
AC XY:
107
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00547
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00216
Gnomad4 NFE
AF:
0.00223
Gnomad4 OTH
AF:
0.000956
Alfa
AF:
0.00169
Hom.:
11
Bravo
AF:
0.00102
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00140
AC:
12
ExAC
AF:
0.00156
AC:
190
EpiCase
AF:
0.00185
EpiControl
AF:
0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Chédiak-Higashi syndrome Uncertain:2Benign:1
Dec 08, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

LYST NM_000081.3 exon23 p.Gln2237Pro (c.6710A>C): This variant has not been reported in the literature but is present in 0.2% (285/128512) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-235922443-T-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:211411). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:1
Jun 16, 2015
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 21, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: LYST c.6710A>C (p.Gln2237Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 282064 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LYST causing Chediak-Higashi Syndrome (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.6710A>C has been reported in the literature in an individual with suspected Inherited Bleeding Disorders without evidence for causality (Leinoe_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28748566). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The LYST p.Gln2237Pro variant was not identified in the literature nor was it identified in Cosmic. The variant was found in dbSNP (ID: rs138443479), LOVD 3.0 and in ClinVar (classified as Likely Benign by Invitae and as a VUS by Genetics Services Laboratory (University of Chicago) and Illumina for Chédiak-Higashi syndrome). The variant was identified in control databases in 430 of 282064 chromosomes (2 homozygous) at a frequency of 0.001524 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 49 of 10346 chromosomes (freq: 0.004736), European (Finnish) in 71 of 25108 chromosomes (freq: 0.002828), European (non-Finnish) in 285 of 128512 chromosomes (freq: 0.002218), Other in 11 of 7202 chromosomes (freq: 0.001527), Latino in 10 of 35378 chromosomes (freq: 0.000283) and African in 4 of 24966 chromosomes (freq: 0.00016), while the variant was not observed in the East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer); SpliceSiteFinder-like and MaxEntScan, predict the shift of a 3' splice site from c.6711 to c.6716. However, this information is not very predictive of pathogenicity. The p.Gln2237 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is also not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would suggest a more benign role for this variant. This variant is classified as likely benign. -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

LYST: BP4, BS2 -

Meniere disease Uncertain:1
Jun 03, 2024
Center for Computational Biology & Bioinformatics, University of California, San Diego
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

LYST-related disorder Benign:1
Jun 24, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1
Mar 07, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autoinflammatory syndrome Benign:1
Sep 01, 2018
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.073
T
MetaSVM
Benign
-0.33
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.35
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.99
D
Vest4
0.84
MVP
0.81
ClinPred
0.053
T
GERP RS
3.8
Varity_R
0.31
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138443479; hg19: chr1-235922443; API