rs374628146

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_005045.4(RELN):​c.6031C>T​(p.Arg2011Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2011H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.98
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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RELNNM_005045.4 linkc.6031C>T p.Arg2011Cys missense_variant Exon 40 of 65 ENST00000428762.6 NP_005036.2 P78509-1
RELNNM_173054.3 linkc.6031C>T p.Arg2011Cys missense_variant Exon 40 of 64 NP_774959.1 P78509-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RELNENST00000428762.6 linkc.6031C>T p.Arg2011Cys missense_variant Exon 40 of 65 5 NM_005045.4 ENSP00000392423.1 P78509-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251358
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461624
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152284
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Mar 15, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Unlikely to be causative of RELN-related lateral temporal epilepsy (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Uncertain:1
May 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2011 of the RELN protein (p.Arg2011Cys). This variant is present in population databases (rs374628146, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RELN-related conditions. ClinVar contains an entry for this variant (Variation ID: 475975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RELN protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Jul 06, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.034
D
MetaRNN
Uncertain
0.43
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Uncertain
2.1
M;M;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Benign
0.26
Sift
Uncertain
0.0080
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.41
MVP
0.67
MPC
0.25
ClinPred
0.67
D
GERP RS
5.6
Varity_R
0.21
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs374628146; hg19: chr7-103193949; COSMIC: COSV58999295; API