rs201296719
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting
The NM_005045.4(RELN):c.4893C>G(p.Asp1631Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000638 in 1,613,948 control chromosomes in the GnomAD database, including 1 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. D1631N) has been classified as Uncertain significance.
Frequency
Consequence
NM_005045.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RELN | NM_005045.4 | c.4893C>G | p.Asp1631Glu | missense_variant | 33/65 | ENST00000428762.6 | |
RELN | NM_173054.3 | c.4893C>G | p.Asp1631Glu | missense_variant | 33/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RELN | ENST00000428762.6 | c.4893C>G | p.Asp1631Glu | missense_variant | 33/65 | 5 | NM_005045.4 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000104 AC: 26AN: 250604Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135462
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461656Hom.: 1 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727138
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74474
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 30181556, 28404951) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RELN p.Asp1631Glu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs201296719, Uncertain significance) and in ClinVar (classified as a VUS by the Genetic Services Laboratory at the University of Chicago in 2015 and by Invitae in 2018). The variant was identified in control databases in 29 of 282000 chromosomes at a frequency of 0.000103 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 15 of 10342 chromosomes (freq: 0.00145), Other in 3 of 7196 chromosomes (freq: 0.000417), Latino in 7 of 35390 chromosomes (freq: 0.000198) and European (non-Finnish) in 4 of 128492 chromosomes (freq: 0.000031); it was not observed in the African, East Asian, European (Finnish), and South Asian populations. The p.Asp1631 residue is conserved in mammals and other organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 05, 2015 | - - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at