rs115640958

Positions:

chr7-103515218-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005045.4(RELN):c.8086G>A(p.Ala2696Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,614,142 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 24 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.74

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=0.0038847327).

BP6

Variant 7-103515218-C-T is Benign according to our data. Variant chr7-103515218-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103515218-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1708/152250) while in subpopulation AFR AF= 0.0392 (1626/41528). AF 95% confidence interval is 0.0376. There are 28 homozygotes in gnomad4. There are 819 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.8086G>A	p.Ala2696Thr	missense_variant	50/65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.8086G>A	p.Ala2696Thr	missense_variant	50/64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.8086G>A	p.Ala2696Thr	missense_variant	50/65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1704

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0392

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00282

AC:

709

AN:

251220

Hom.:

AF XY:

0.00201

AC XY:

273

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00112

AC:

1639

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

703

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0410

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.0112

AC:

1708

AN:

152250

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

819

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0392

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00245

Hom.:

Bravo

AF:

0.0127

ESP6500AA

AF:

0.0356

AC:

157

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00364

AC:

442

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 23, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Norman-Roberts syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.077

T;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.51

P;B;.

Vest4

0.65

MVP

0.27

MPC

0.32

ClinPred

0.0076

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.075

gMVP

0.31

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