chr7-103652718-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005045.4(RELN):c.1596G>A(p.Gln532Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,612,708 control chromosomes in the GnomAD database, including 866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 157 hom., cov: 32)

Exomes 𝑓: 0.028 ( 709 hom. )

Consequence

RELN
NM_005045.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.20

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 Gene-Disease associations (from GenCC):

lissencephaly with cerebellar hypoplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Norman-Roberts syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
familial temporal lobe epilepsy 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ankylosing spondylitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 7-103652718-C-T is Benign according to our data. Variant chr7-103652718-C-T is described in ClinVar as Benign. ClinVar VariationId is 95212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.1596G>A	p.Gln532Gln	synonymous_variant	Exon 14 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3 link	c.1596G>A	p.Gln532Gln	synonymous_variant	Exon 14 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.1596G>A	p.Gln532Gln	synonymous_variant	Exon 14 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes

AF:

0.0385

AC:

5854

AN:

151958

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0712

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0286

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00893

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0305

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0237

AC:

5938

AN:

250726

AF XY:

0.0224

show subpopulations

Gnomad AFR exome

AF:

0.0716

Gnomad AMR exome

AF:

0.0139

Gnomad ASJ exome

AF:

0.0187

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0288

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0281

AC:

41046

AN:

1460632

Hom.:

709

Cov.:

AF XY:

0.0274

AC XY:

19902

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.0739

AC:

2468

AN:

33408

American (AMR)

AF:

0.0152

AC:

679

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

495

AN:

26068

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39666

South Asian (SAS)

AF:

0.00850

AC:

733

AN:

86238

European-Finnish (FIN)

AF:

0.0224

AC:

1197

AN:

53414

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0304

AC:

33817

AN:

1111190

Other (OTH)

AF:

0.0264

AC:

1592

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2160

4321

6481

8642

10802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1256

2512

3768

5024

6280

<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:

0.0385

AC:

5853

AN:

152076

Hom.:

157

Cov.:

AF XY:

0.0372

AC XY:

2765

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0710

AC:

2945

AN:

41508

American (AMR)

AF:

0.0286

AC:

436

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3466

East Asian (EAS)

AF:

0.000582

AC:

AN:

5156

South Asian (SAS)

AF:

0.00894

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0208

AC:

221

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0305

AC:

2073

AN:

67952

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

278

557

835

1114

1392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0338

Hom.:

Bravo

AF:

0.0404

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0290

EpiControl

AF:

0.0252

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 28, 2014

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. -

Feb 23, 2013

Eurofins Ntd Llc (ga)

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

- -

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. -

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 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.9

(source)

DANN

Benign

0.68

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over