rs115640958

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.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. 13/21 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

Publications

3 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 links:

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

SLC26A5-AS1 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=0.0038847327).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 65	NP_005036.2
	RELN	NM_173054.3		c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 64	NP_774959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RELN	ENST00000428762.6	TSL:5 MANE Select	c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 65	ENSP00000392423.1
RELN	ENST00000424685.3	TSL:5	c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 65	ENSP00000388446.3
RELN	ENST00000343529.9	TSL:5	c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 64	ENSP00000345694.5

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

GnomAD2 exomes

AF:

0.00282

AC:

709

AN:

251220

AF XY:

0.00201

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 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

African (AFR)

AF:

0.0410

AC:

1374

AN:

33480

American (AMR)

AF:

0.00199

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112012

Other (OTH)

AF:

0.00232

AC:

140

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

103

206

309

412

515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0112

AC:

1708

AN:

152250

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

819

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0392

AC:

1626

AN:

41528

American (AMR)

AF:

0.00366

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68026

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00469

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

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 26, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Norman-Roberts syndrome

Benign:1

Jan 12, 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.

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;CN030884:Epilepsy, familial temporal lobe, 1

Benign:1

Nov 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.077

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

3.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.50

REVEL

Benign

0.026

Sift

Benign

0.10

Sift4G

Benign

0.31

Polyphen

0.51

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

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over