rs77310684
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_014159.7(SETD2):c.578C>T(p.Pro193Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0007 in 1,551,882 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.00053 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 19 hom. )
Consequence
SETD2
NM_014159.7 missense
NM_014159.7 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 4.27
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 Benign. Variant got -19 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SETD2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0076925457).
BP6
?
Variant 3-47124058-G-A is Benign according to our data. Variant chr3-47124058-G-A is described in ClinVar as [Benign]. Clinvar id is 475527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000525 (80/152236) while in subpopulation EAS AF= 0.0137 (71/5174). AF 95% confidence interval is 0.0112. There are 2 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 80 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETD2 | NM_014159.7 | c.578C>T | p.Pro193Leu | missense_variant | 3/21 | ENST00000409792.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETD2 | ENST00000409792.4 | c.578C>T | p.Pro193Leu | missense_variant | 3/21 | 5 | NM_014159.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000526 AC: 80AN: 152118Hom.: 2 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000951 AC: 150AN: 157722Hom.: 1 AF XY: 0.000888 AC XY: 74AN XY: 83318
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GnomAD4 exome AF: 0.000719 AC: 1006AN: 1399646Hom.: 19 Cov.: 33 AF XY: 0.000697 AC XY: 481AN XY: 690326
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GnomAD4 genome ? AF: 0.000526 AC: 80AN: 152236Hom.: 2 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74430
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Luscan-Lumish syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | SETD2: BP4, BS1, BS2 - |
SETD2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 23, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
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