rs79499902
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_005045.4(RELN):c.5284G>A(p.Val1762Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00413 in 1,565,482 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.010 ( 16 hom., cov: 30)
Exomes 𝑓: 0.0035 ( 32 hom. )
Consequence
RELN
NM_005045.4 missense
NM_005045.4 missense
Scores
4
14
Clinical Significance
Conservation
PhyloP100: 4.57
Genes affected
RELN (HGNC:9957): (reelin) This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 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, RELN
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0073706806).
BP6
?
Variant 7-103561880-C-T is Benign according to our data. Variant chr7-103561880-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103561880-C-T is described in Lovd as [Benign]. Variant chr7-103561880-C-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1480/146512) while in subpopulation AFR AF= 0.0274 (1093/39888). AF 95% confidence interval is 0.0261. There are 16 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 16 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RELN | NM_005045.4 | c.5284G>A | p.Val1762Ile | missense_variant | 35/65 | ENST00000428762.6 | |
RELN | NM_173054.3 | c.5284G>A | p.Val1762Ile | missense_variant | 35/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RELN | ENST00000428762.6 | c.5284G>A | p.Val1762Ile | missense_variant | 35/65 | 5 | NM_005045.4 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.0101 AC: 1477AN: 146398Hom.: 16 Cov.: 30
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GnomAD3 exomes AF: 0.00475 AC: 1192AN: 251180Hom.: 11 AF XY: 0.00440 AC XY: 598AN XY: 135762
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GnomAD4 exome AF: 0.00352 AC: 4989AN: 1418970Hom.: 32 Cov.: 34 AF XY: 0.00354 AC XY: 2499AN XY: 706156
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GnomAD4 genome ? AF: 0.0101 AC: 1480AN: 146512Hom.: 16 Cov.: 30 AF XY: 0.0101 AC XY: 715AN XY: 70948
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 27, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 13, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RELN p.Val1762Ile variant was not identified in the literature but was identified in dbSNP (ID: rs79499902), LOVD 3.0 and ClinVar (classified as benign by Prevention Genetics, Genetic Services Laboratory, University of Chicago, GeneDx, EGL Genetic Diagnostics, and Invitae, as likely benign by Athena Diagnostics Inc and Illumina and as pathogenic by Bioinformatics Core, Luxembourg Center for Systems Biomedicine). The variant was identified in control databases in 1463 of 282336 chromosomes (13 homozygous) at a frequency of 0.005182 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 687 of 24876 chromosomes (freq: 0.02762), Ashkenazi Jewish in 116 of 10364 chromosomes (freq: 0.01119), Latino in 138 of 35352 chromosomes (freq: 0.003904), Other in 27 of 7208 chromosomes (freq: 0.003746), European (non-Finnish) in 413 of 128966 chromosomes (freq: 0.003202), South Asian in 78 of 30612 chromosomes (freq: 0.002548), European (Finnish) in 3 of 25064 chromosomes (freq: 0.00012), and East Asian in 1 of 19894 chromosomes (freq: 0.00005). The p.Val1762 residue is conserved in mammals and 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 this variant meets our laboratory's criteria to be classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 01, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 19, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Childhood epilepsy with centrotemporal spikes Pathogenic:1
Pathogenic, no assertion criteria provided | case-control | Bioinformatics Core, Luxembourg Center for Systems Biomedicine | Jan 01, 2017 | CAADphred>15 - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Norman-Roberts syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | RELN: BS1, BS2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;.
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