rs2711885

Variant summary

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

The NM_005045.4(RELN):c.8843+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,613,976 control chromosomes in the GnomAD database, including 786,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74597 hom., cov: 32)

Exomes 𝑓: 0.99 ( 711416 hom. )

Consequence

RELN
NM_005045.4 splice_region, intron

Scores

Splicing: ADA: 0.00001489

Clinical Significance

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

Conservation

PhyloP100: 0.100

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:

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

SLC26A5-AS1 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 (BayesDel_noAF=-0.89).

BP6

Variant 7-103498070-C-G is Benign according to our data. Variant chr7-103498070-C-G is described in ClinVar as [Benign]. Clinvar id is 95234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103498070-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
RELN	NM_005045.4 linkuse as main transcript	c.8843+7G>C	splice_region_variant, intron_variant	ENST00000428762.6
SLC26A5-AS1	NR_110141.1 linkuse as main transcript	n.1366-6334C>G	intron_variant, non_coding_transcript_variant
RELN	NM_173054.3 linkuse as main transcript	c.8843+7G>C	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.8843+7G>C		splice_region_variant, intron_variant		5	NM_005045.4	P5	P78509-1
SLC26A5-AS1	ENST00000422488.1 linkuse as main transcript	n.1366-6334C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.990

AC:

150621

AN:

152198

Hom.:

74537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.997

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.994

Gnomad ASJ

AF:

0.975

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.992

Gnomad FIN

AF:

0.977

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.986

Gnomad OTH

AF:

0.988

GnomAD3 exomes

AF:

0.987

AC:

247858

AN:

251068

Hom.:

122367

AF XY:

0.987

AC XY:

133917

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

0.995

Gnomad ASJ exome

AF:

0.978

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.990

Gnomad FIN exome

AF:

0.973

Gnomad NFE exome

AF:

0.985

Gnomad OTH exome

AF:

0.982

GnomAD4 exome

AF:

0.987

AC:

1442059

AN:

1461660

Hom.:

711416

Cov.:

AF XY:

0.987

AC XY:

717415

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.998

Gnomad4 AMR exome

AF:

0.995

Gnomad4 ASJ exome

AF:

0.978

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.990

Gnomad4 FIN exome

AF:

0.971

Gnomad4 NFE exome

AF:

0.986

Gnomad4 OTH exome

AF:

0.987

GnomAD4 genome

AF:

0.990

AC:

150741

AN:

152316

Hom.:

74597

Cov.:

AF XY:

0.990

AC XY:

73739

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.997

Gnomad4 AMR

AF:

0.994

Gnomad4 ASJ

AF:

0.975

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.992

Gnomad4 FIN

AF:

0.977

Gnomad4 NFE

AF:

0.986

Gnomad4 OTH

AF:

0.988

Alfa

AF:

0.985

Hom.:

23935

Bravo

AF:

0.991

Asia WGS

AF:

0.995

AC:

3461

AN:

3478

EpiCase

AF:

0.985

EpiControl

AF:

0.986

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -

Norman-Roberts syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

Cadd

Benign

1.7

Dann

Benign

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.0

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