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
Consequence
NM_000081.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00138 AC: 210AN: 152230Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00138 AC: 346AN: 250670Hom.: 1 AF XY: 0.00136 AC XY: 184AN XY: 135438
GnomAD4 exome AF: 0.00132 AC: 1926AN: 1461840Hom.: 4 Cov.: 33 AF XY: 0.00133 AC XY: 970AN XY: 727218
GnomAD4 genome AF: 0.00138 AC: 210AN: 152230Hom.: 2 Cov.: 32 AF XY: 0.00144 AC XY: 107AN XY: 74384
ClinVar
Submissions by phenotype
Chédiak-Higashi syndrome Uncertain:2Benign:1
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 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 16, 2015 | - - |
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. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2025 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at