rs56342240

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005045.4(RELN):c.3651C>G(p.Ile1217Met) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,996 control chromosomes in the GnomAD database, including 17 homozygotes. 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 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 16 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 6.15

Publications

17 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014514536).

BP6

Variant 7-103594381-G-C is Benign according to our data. Variant chr7-103594381-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95218.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00276 (420/152284) while in subpopulation NFE AF = 0.00528 (359/68022). AF 95% confidence interval is 0.00483. There are 1 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.3651C>G	p.Ile1217Met	missense_variant	Exon 26 of 65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.3651C>G	p.Ile1217Met	missense_variant	Exon 26 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.3651C>G	p.Ile1217Met	missense_variant	Exon 26 of 65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

420

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00528

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00247

AC:

619

AN:

251098

AF XY:

0.00240

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00474

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00406

AC:

5931

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

2879

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33474

American (AMR)

AF:

0.000649

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000591

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000805

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00500

AC:

5560

AN:

1111876

Other (OTH)

AF:

0.00339

AC:

205

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

304

609

913

1218

1522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00276

AC:

420

AN:

152284

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41558

American (AMR)

AF:

0.000719

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00528

AC:

359

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00420

Hom.:

Bravo

AF:

0.00266

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00268

AC:

326

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00387

EpiControl

AF:

0.00368

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25648840, 26302956) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RELN: BS1, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jan 27, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 05, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Norman-Roberts syndrome

Benign:2

May 09, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.30

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

6.1

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.3

N;N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.66

P;P;.

Vest4

0.89

MVP

0.13

MPC

0.46

ClinPred

0.027

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.67

Mutation Taster

=77/23

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