1-235759143-T-G
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_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).
Frequency
Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 4 hom. )
Consequence
LYST
NM_000081.4 missense
NM_000081.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 7.19
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LYST. . Trascript score misZ 4.0845 (greater than threshold 3.09). GenCC has associacion of gene with Chediak-Higashi syndrome, attenuated Chédiak-Higashi syndrome.
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: {Likely_benign=5, Uncertain_significance=3}. 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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LYST | NM_000081.4 | c.6710A>C | p.Gln2237Pro | missense_variant | 23/53 | ENST00000389793.7 | NP_000072.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LYST | ENST00000389793.7 | c.6710A>C | p.Gln2237Pro | missense_variant | 23/53 | 5 | NM_000081.4 | ENSP00000374443 | P1 |
Frequencies
GnomAD3 genomes 0.00138 AC: 210AN: 152230Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00138 AC: 346AN: 250670Hom.: 1 AF XY: 0.00136 AC XY: 184AN XY: 135438
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GnomAD4 exome AF: 0.00132 AC: 1926AN: 1461840Hom.: 4 Cov.: 33 AF XY: 0.00133 AC XY: 970AN XY: 727218
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GnomAD4 genome 0.00138 AC: 210AN: 152230Hom.: 2 Cov.: 32 AF XY: 0.00144 AC XY: 107AN XY: 74384
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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
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 08, 2021 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 21, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 16, 2015 | - - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | LYST: BP4, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Meniere disease Uncertain:1
| Uncertain significance, no assertion criteria provided | research | Center for Computational Biology & Bioinformatics, University of California, San Diego | Jun 03, 2024 | - - |
LYST-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 24, 2022 | 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
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2022 | 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
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at