rs575862721
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_014159.7(SETD2):c.1833G>T(p.Lys611Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,124 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K611K) has been classified as Likely benign.
Frequency
Consequence
NM_014159.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETD2 | NM_014159.7 | c.1833G>T | p.Lys611Asn | missense_variant | 3/21 | ENST00000409792.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETD2 | ENST00000409792.4 | c.1833G>T | p.Lys611Asn | missense_variant | 3/21 | 5 | NM_014159.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000444 AC: 11AN: 247910Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134594
GnomAD4 exome AF: 0.0000726 AC: 106AN: 1460932Hom.: 0 Cov.: 33 AF XY: 0.0000771 AC XY: 56AN XY: 726752
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74358
ClinVar
Submissions by phenotype
Luscan-Lumish syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 18, 2020 | The p.Lys611Asn variant identified in SETD2 has not been reported in affected individuals in the literature. The variant has 0.000043 allele frequency in gnomAD database (12 out of 279,304 heterozygous alleles) indicating it is a rare allele in general population. The variant affects a moderately conserved residue andin silico prediction tools show conflicting interpretations about pathogenicity of this variant. Based on the current evidence, the p.Lys611Asn variant in the SETD2 gene is assessed as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2020 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SETD2-related conditions. This variant is present in population databases (rs575862721, ExAC 0.006%). This sequence change replaces lysine with asparagine at codon 611 of the SETD2 protein (p.Lys611Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at