rs2075043

Positions:

chr7-103540425-A-G

Variant summary

Our verdict is Benign. Variant got -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

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:

RELN (HGNC:):

RELN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103540425-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
RELN	NM_005045.4 linkuse as main transcript	c.6702T>C	p.Cys2234Cys	synonymous_variant	44/65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 linkuse as main transcript	c.6702T>C	p.Cys2234Cys	synonymous_variant	44/64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.6702T>C	p.Cys2234Cys	synonymous_variant	44/65	5	NM_005045.4	ENSP00000392423.1		P78509-1

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

GnomAD3 exomes

AF:

0.0787

AC:

19759

AN:

251062

Hom.:

1192

AF XY:

0.0763

AC XY:

10355

AN XY:

135726

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 SAS exome

AF:

0.0842

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

Gnomad4 AFR exome

AF:

0.0479

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.0767

Gnomad4 EAS exome

AF:

0.199

Gnomad4 SAS exome

AF:

0.0817

Gnomad4 FIN exome

AF:

0.0969

Gnomad4 NFE exome

AF:

0.0420

Gnomad4 OTH exome

AF:

0.0632

GnomAD4 genome

AF:

0.0622

AC:

9464

AN:

152224

Hom.:

428

Cov.:

AF XY:

0.0652

AC XY:

4851

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0510

Gnomad4 AMR

AF:

0.0864

Gnomad4 ASJ

AF:

0.0692

Gnomad4 EAS

AF:

0.250

Gnomad4 SAS

AF:

0.0837

Gnomad4 FIN

AF:

0.0925

Gnomad4 NFE

AF:

0.0435

Gnomad4 OTH

AF:

0.0654

Alfa

AF:

0.0522

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 08, 2018	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Norman-Roberts syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

DANN

Benign

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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