rs115640958

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005045.4(RELN):​c.8086G>A​(p.Ala2696Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,614,142 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 24 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

3
15

Clinical Significance

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

Conservation

PhyloP100: 3.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0038847327).
BP6
Variant 7-103515218-C-T is Benign according to our data. Variant chr7-103515218-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103515218-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1708/152250) while in subpopulation AFR AF= 0.0392 (1626/41528). AF 95% confidence interval is 0.0376. There are 28 homozygotes in gnomad4. There are 819 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RELNNM_005045.4 linkc.8086G>A p.Ala2696Thr missense_variant 50/65 ENST00000428762.6 NP_005036.2 P78509-1
RELNNM_173054.3 linkc.8086G>A p.Ala2696Thr missense_variant 50/64 NP_774959.1 P78509-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RELNENST00000428762.6 linkc.8086G>A p.Ala2696Thr missense_variant 50/655 NM_005045.4 ENSP00000392423.1 P78509-1

Frequencies

GnomAD3 genomes
AF:
0.0112
AC:
1704
AN:
152132
Hom.:
29
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0392
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00367
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:
0.0000588
Gnomad OTH
AF:
0.0105
GnomAD3 exomes
AF:
0.00282
AC:
709
AN:
251220
Hom.:
16
AF XY:
0.00201
AC XY:
273
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.0395
Gnomad AMR exome
AF:
0.00159
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.00112
AC:
1639
AN:
1461892
Hom.:
24
Cov.:
31
AF XY:
0.000967
AC XY:
703
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0410
Gnomad4 AMR exome
AF:
0.00199
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00232
GnomAD4 genome
AF:
0.0112
AC:
1708
AN:
152250
Hom.:
28
Cov.:
32
AF XY:
0.0110
AC XY:
819
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0392
Gnomad4 AMR
AF:
0.00366
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.0104
Alfa
AF:
0.00245
Hom.:
9
Bravo
AF:
0.0127
ESP6500AA
AF:
0.0356
AC:
157
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00364
AC:
442
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 26, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 23, 2021- -
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Norman-Roberts syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
21
DANN
Benign
0.94
DEOGEN2
Benign
0.077
T;.;.
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.038
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
D;D;D
MetaRNN
Benign
0.0039
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;L;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.50
N;N;N
REVEL
Benign
0.026
Sift
Benign
0.10
T;T;T
Sift4G
Benign
0.31
T;T;T
Polyphen
0.51
P;B;.
Vest4
0.65
MVP
0.27
MPC
0.32
ClinPred
0.0076
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.075
gMVP
0.31

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: rs115640958; hg19: chr7-103155665; API