rs201447642
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting
The NM_006267.5(RANBP2):āc.2894A>Gā(p.Asn965Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. N965N) has been classified as Likely benign.
Frequency
Consequence
NM_006267.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RANBP2 | NM_006267.5 | c.2894A>G | p.Asn965Ser | missense_variant | 20/29 | ENST00000283195.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RANBP2 | ENST00000283195.11 | c.2894A>G | p.Asn965Ser | missense_variant | 20/29 | 1 | NM_006267.5 | P1 | |
RANBP2 | ENST00000697737.1 | c.2602+4885A>G | intron_variant | ||||||
RANBP2 | ENST00000697740.1 | c.2524+4885A>G | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152098Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000116 AC: 29AN: 251030Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135644
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461816Hom.: 0 Cov.: 34 AF XY: 0.0000701 AC XY: 51AN XY: 727204
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152098Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74294
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2021 | The c.2894A>G (p.N965S) alteration is located in exon 20 (coding exon 20) of the RANBP2 gene. This alteration results from a A to G substitution at nucleotide position 2894, causing the asparagine (N) at amino acid position 965 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial acute necrotizing encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2021 | 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RANBP2-related disease. This variant is present in population databases (rs201447642, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces asparagine with serine at codon 965 of the RANBP2 protein (p.Asn965Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at