rs201422815
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting
The NM_005045.4(RELN):c.6726G>C(p.Arg2242Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,982 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
RELN
NM_005045.4 missense
NM_005045.4 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 0.401
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 Likely_benign. Variant got -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, RELN
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19579405).
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000191 (29/152140) while in subpopulation AMR AF= 0.00177 (27/15270). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RELN | NM_005045.4 | c.6726G>C | p.Arg2242Ser | missense_variant | 44/65 | ENST00000428762.6 | |
RELN | NM_173054.3 | c.6726G>C | p.Arg2242Ser | missense_variant | 44/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RELN | ENST00000428762.6 | c.6726G>C | p.Arg2242Ser | missense_variant | 44/65 | 5 | NM_005045.4 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000227 AC: 57AN: 251308Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135826
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GnomAD4 exome AF: 0.000106 AC: 155AN: 1461842Hom.: 0 Cov.: 32 AF XY: 0.0000976 AC XY: 71AN XY: 727226
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GnomAD4 genome ? AF: 0.000191 AC: 29AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 15, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 23, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 03, 2014 | - - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;D;T
Sift4G
Uncertain
D;D;D
Polyphen
B;D;.
Vest4
MutPred
Gain of disorder (P = 0.0575);Gain of disorder (P = 0.0575);Gain of disorder (P = 0.0575);
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