rs79499902

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 12/21 in silico tools predict 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 4.57

Publications

15 publications found

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]

RELN Gene-Disease associations (from GenCC):

lissencephaly with cerebellar hypoplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Norman-Roberts syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
familial temporal lobe epilepsy 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ankylosing spondylitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId is 130127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.5284G>A	p.Val1762Ile	missense_variant	Exon 35 of 65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.5284G>A	p.Val1762Ile	missense_variant	Exon 35 of 64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.5284G>A	p.Val1762Ile	missense_variant	Exon 35 of 65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1477

AN:

146398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00646

Gnomad ASJ

AF:

0.00958

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00206

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0164

Gnomad NFE

AF:

0.00336

Gnomad OTH

AF:

0.0113

GnomAD2 exomes

AF:

0.00475

AC:

1192

AN:

251180

AF XY:

0.00440

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.00374

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00352

AC:

4989

AN:

1418970

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2499

AN XY:

706156

show subpopulations

African (AFR)

AF:

0.0302

AC:

969

AN:

32138

American (AMR)

AF:

0.00423

AC:

184

AN:

43464

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

318

AN:

24152

East Asian (EAS)

AF:

0.00

AC:

AN:

36048

South Asian (SAS)

AF:

0.00259

AC:

222

AN:

85848

European-Finnish (FIN)

AF:

0.000202

AC:

AN:

49614

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

0.00263

AC:

2858

AN:

1084870

Other (OTH)

AF:

0.00599

AC:

343

AN:

57290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

293

586

878

1171

1464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0101

AC:

1480

AN:

146512

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

715

AN XY:

70948

show subpopulations

African (AFR)

AF:

0.0274

AC:

1093

AN:

39888

American (AMR)

AF:

0.00645

AC:

AN:

14270

Ashkenazi Jewish (ASJ)

AF:

0.00958

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

4740

South Asian (SAS)

AF:

0.00206

AC:

AN:

4374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9354

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00336

AC:

226

AN:

67212

Other (OTH)

AF:

0.0112

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00593

Hom.:

Bravo

AF:

0.0115

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00516

AC:

626

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Nov 19, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 01, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RELN: BS1, BS2 -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

CAADphred>15 -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Norman-Roberts syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;CN030884:Epilepsy, familial temporal lobe, 1

Benign:1

Nov 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

-0.039

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.77

N;N;.

PhyloP100

4.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.062

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.30

MVP

0.068

MPC

0.14

ClinPred

0.012

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.41

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over