7-103610714-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005045.4(RELN):c.2989C>G(p.Leu997Val) variant causes a missense change. The variant allele was found at a frequency of 0.11 in 1,581,198 control chromosomes in the GnomAD database, including 10,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 918 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9180 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.11

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014434159).

BP6

Variant 7-103610714-G-C is Benign according to our data. Variant chr7-103610714-G-C is described in ClinVar as [Benign]. Clinvar id is 130119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103610714-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.2989C>G	p.Leu997Val	missense_variant	Exon 22 of 65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.2989C>G	p.Leu997Val	missense_variant	Exon 22 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.2989C>G	p.Leu997Val	missense_variant	Exon 22 of 65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16029

AN:

152044

Hom.:

921

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0843

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.0848

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.0993

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.116

AC:

28983

AN:

250826

Hom.:

1830

AF XY:

0.118

AC XY:

15992

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.0814

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.0940

Gnomad EAS exome

AF:

0.130

Gnomad SAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.0973

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.111

AC:

158211

AN:

1429036

Hom.:

9180

Cov.:

AF XY:

0.112

AC XY:

80087

AN XY:

712990

show subpopulations

Gnomad4 AFR exome

AF:

0.0825

Gnomad4 AMR exome

AF:

0.111

Gnomad4 ASJ exome

AF:

0.0913

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.157

Gnomad4 FIN exome

AF:

0.0985

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.115

GnomAD4 genome

AF:

0.105

AC:

16025

AN:

152162

Hom.:

918

Cov.:

AF XY:

0.105

AC XY:

7847

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0840

Gnomad4 AMR

AF:

0.119

Gnomad4 ASJ

AF:

0.0848

Gnomad4 EAS

AF:

0.129

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.0993

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.0814

Hom.:

229

Bravo

AF:

0.104

TwinsUK

AF:

0.108

AC:

399

ALSPAC

AF:

0.114

AC:

439

ESP6500AA

AF:

0.0833

AC:

367

ESP6500EA

AF:

0.104

AC:

893

ExAC

AF:

0.116

AC:

14120

Asia WGS

AF:

0.170

AC:

588

AN:

3476

EpiCase

AF:

0.104

EpiControl

AF:

0.105

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Sep 06, 2018

Eurofins Ntd Llc (ga)

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

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 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. -

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

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

- -

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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.079

T;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.46

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.19

B;B;.

Vest4

0.059

MPC

0.17

ClinPred

0.010

GERP RS

4.4

Varity_R

0.065

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over