rs115734214

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.1888A>C(p.Ser630Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,611,042 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S630S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 42 hom., cov: 32)

Exomes 𝑓: 0.031 ( 764 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.67

Publications

12 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=0.009536654).

BP6

Variant 7-103651665-T-G is Benign according to our data. Variant chr7-103651665-T-G is described in ClinVar as Benign. ClinVar VariationId is 130116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3400/152104) while in subpopulation NFE AF = 0.0312 (2118/67948). AF 95% confidence interval is 0.0301. There are 42 homozygotes in GnomAd4. There are 1655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.1888A>C	p.Ser630Arg	missense_variant	Exon 15 of 65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.1888A>C	p.Ser630Arg	missense_variant	Exon 15 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.1888A>C	p.Ser630Arg	missense_variant	Exon 15 of 65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3400

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00640

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0312

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0255

AC:

6376

AN:

250344

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.00567

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.0283

Gnomad FIN exome

AF:

0.0387

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0311

AC:

45316

AN:

1458938

Hom.:

764

Cov.:

AF XY:

0.0306

AC XY:

22243

AN XY:

725896

show subpopulations

African (AFR)

AF:

0.00518

AC:

173

AN:

33366

American (AMR)

AF:

0.0163

AC:

725

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.0151

AC:

393

AN:

26048

East Asian (EAS)

AF:

0.0232

AC:

918

AN:

39630

South Asian (SAS)

AF:

0.0193

AC:

1660

AN:

86218

European-Finnish (FIN)

AF:

0.0367

AC:

1959

AN:

53350

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0341

AC:

37797

AN:

1109824

Other (OTH)

AF:

0.0275

AC:

1654

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1951

3903

5854

7806

9757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1444

2888

4332

5776

7220

<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:

0.0224

AC:

3400

AN:

152104

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1655

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00638

AC:

265

AN:

41538

American (AMR)

AF:

0.0230

AC:

350

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3468

East Asian (EAS)

AF:

0.0250

AC:

129

AN:

5150

South Asian (SAS)

AF:

0.0159

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0337

AC:

358

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0312

AC:

2118

AN:

67948

Other (OTH)

AF:

0.0185

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

180

360

541

721

901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0281

Hom.:

236

Bravo

AF:

0.0209

TwinsUK

AF:

0.0405

AC:

150

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0328

AC:

282

ExAC

AF:

0.0249

AC:

3021

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0295

EpiControl

AF:

0.0298

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2013

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 02, 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

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

7.7

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.029

D;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.33

MutPred

0.37

Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);

MPC

0.73

ClinPred

0.0090

GERP RS

5.6

Varity_R

0.41

gMVP

0.75

Mutation Taster

=98/2

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