rs114494558

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_005045.4(RELN):​c.906C>T​(p.Ala302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,613,654 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

RELN
NM_005045.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.486
Variant links:
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 -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 7-103698090-G-A is Benign according to our data. Variant chr7-103698090-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103698090-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.486 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00261 (397/152242) while in subpopulation AFR AF= 0.00927 (385/41552). AF 95% confidence interval is 0.0085. There are 0 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RELNNM_005045.4 linkuse as main transcriptc.906C>T p.Ala302= synonymous_variant 10/65 ENST00000428762.6 NP_005036.2
RELNNM_173054.3 linkuse as main transcriptc.906C>T p.Ala302= synonymous_variant 10/64 NP_774959.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RELNENST00000428762.6 linkuse as main transcriptc.906C>T p.Ala302= synonymous_variant 10/655 NM_005045.4 ENSP00000392423 P5P78509-1

Frequencies

GnomAD3 genomes
AF:
0.00261
AC:
397
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00929
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000682
AC:
171
AN:
250812
Hom.:
0
AF XY:
0.000517
AC XY:
70
AN XY:
135520
show subpopulations
Gnomad AFR exome
AF:
0.00929
Gnomad AMR exome
AF:
0.000492
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000244
AC:
357
AN:
1461412
Hom.:
0
Cov.:
31
AF XY:
0.000219
AC XY:
159
AN XY:
727004
show subpopulations
Gnomad4 AFR exome
AF:
0.00903
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.000480
GnomAD4 genome
AF:
0.00261
AC:
397
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.00249
AC XY:
185
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.00927
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00148
Hom.:
0
Bravo
AF:
0.00287
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 05, 2016- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 28, 2017This 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 submitterclinical testingEurofins Ntd Llc (ga)Jul 04, 2014- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2024- -
RELN-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 02, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
7.6
DANN
Benign
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs114494558; hg19: chr7-103338537; API