rs765867260
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS1_Supporting
The NM_014159.7(SETD2):c.3193C>T(p.Arg1065Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
SETD2
NM_014159.7 missense
NM_014159.7 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 5.00
Genes affected
SETD2 (HGNC:18420): (SET domain containing 2, histone lysine methyltransferase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SETD2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.35565054).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000197 (3/152082) while in subpopulation EAS AF= 0.000385 (2/5192). AF 95% confidence interval is 0.0000682. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETD2 | NM_014159.7 | c.3193C>T | p.Arg1065Cys | missense_variant | 3/21 | ENST00000409792.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETD2 | ENST00000409792.4 | c.3193C>T | p.Arg1065Cys | missense_variant | 3/21 | 5 | NM_014159.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152082Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250052Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135254
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460246Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 726516
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Luscan-Lumish syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2018 | This sequence change replaces arginine with cysteine at codon 1065 of the SETD2 protein (p.Arg1065Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs765867260, ExAC 0.01%). This variant has not been reported in the literature in individuals with SETD2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;.
Polyphen
B;.
Vest4
MutPred
Gain of glycosylation at S1060 (P = 0.0087);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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