rs2075043

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005045.4(RELN):c.6702T>C(p.Cys2234Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,613,844 control chromosomes in the GnomAD database, including 3,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 428 hom., cov: 32)

Exomes 𝑓: 0.054 ( 3103 hom. )

Consequence

RELN
NM_005045.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.95

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 7-103540425-A-G is Benign according to our data. Variant chr7-103540425-A-G is described in ClinVar as Benign. ClinVar VariationId is 95227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.95 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.6702T>C	p.Cys2234Cys	synonymous_variant	Exon 44 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3 link	c.6702T>C	p.Cys2234Cys	synonymous_variant	Exon 44 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.6702T>C	p.Cys2234Cys	synonymous_variant	Exon 44 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes

AF:

0.0621

AC:

9445

AN:

152106

Hom.:

429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0509

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0862

Gnomad ASJ

AF:

0.0692

Gnomad EAS

AF:

0.251

Gnomad SAS

AF:

0.0826

Gnomad FIN

AF:

0.0925

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0435

Gnomad OTH

AF:

0.0637

GnomAD2 exomes

AF:

0.0787

AC:

19759

AN:

251062

AF XY:

0.0763

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.0735

Gnomad EAS exome

AF:

0.246

Gnomad FIN exome

AF:

0.0933

Gnomad NFE exome

AF:

0.0440

Gnomad OTH exome

AF:

0.0649

GnomAD4 exome

AF:

0.0541

AC:

79103

AN:

1461620

Hom.:

3103

Cov.:

AF XY:

0.0543

AC XY:

39458

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.0479

AC:

1605

AN:

33478

American (AMR)

AF:

0.104

AC:

4667

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0767

AC:

2005

AN:

26134

East Asian (EAS)

AF:

0.199

AC:

7902

AN:

39698

South Asian (SAS)

AF:

0.0817

AC:

7048

AN:

86258

European-Finnish (FIN)

AF:

0.0969

AC:

5163

AN:

53298

Middle Eastern (MID)

AF:

0.0328

AC:

189

AN:

5768

European-Non Finnish (NFE)

AF:

0.0420

AC:

46705

AN:

1111872

Other (OTH)

AF:

0.0632

AC:

3819

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4022

8043

12065

16086

20108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1902

3804

5706

7608

9510

<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:

0.0622

AC:

9464

AN:

152224

Hom.:

428

Cov.:

AF XY:

0.0652

AC XY:

4851

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0510

AC:

2119

AN:

41562

American (AMR)

AF:

0.0864

AC:

1321

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0692

AC:

240

AN:

3470

East Asian (EAS)

AF:

0.250

AC:

1294

AN:

5166

South Asian (SAS)

AF:

0.0837

AC:

404

AN:

4824

European-Finnish (FIN)

AF:

0.0925

AC:

981

AN:

10606

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0435

AC:

2955

AN:

67994

Other (OTH)

AF:

0.0654

AC:

138

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

434

869

1303

1738

2172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0523

Hom.:

Bravo

AF:

0.0610

Asia WGS

AF:

0.145

AC:

504

AN:

3478

EpiCase

AF:

0.0433

EpiControl

AF:

0.0415

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 30, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2014

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

not provided

Benign:2

May 08, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Norman-Roberts syndrome

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.0

(source)

DANN

Benign

0.66

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism (auto)

(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