rs115734214

Positions:

chr7-103651665-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_005045.4(RELN):c.1888A>C(p.Ser630Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,611,042 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 42 hom., cov: 32)

Exomes 𝑓: 0.031 ( 764 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.67

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.

BP4

Computational evidence support a benign effect (MetaRNN=0.009536654).

BP6

Variant 7-103651665-T-G is Benign according to our data. Variant chr7-103651665-T-G is described in ClinVar as [Benign]. Clinvar id is 130116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103651665-T-G is described in Lovd as [Benign]. Variant chr7-103651665-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0224 (3400/152104) while in subpopulation NFE AF= 0.0312 (2118/67948). AF 95% confidence interval is 0.0301. There are 42 homozygotes in gnomad4. There are 1655 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4 linkuse as main transcript	c.1888A>C	p.Ser630Arg	missense_variant	15/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3 linkuse as main transcript	c.1888A>C	p.Ser630Arg	missense_variant	15/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.1888A>C	p.Ser630Arg	missense_variant	15/65	5	NM_005045.4	ENSP00000392423	P5	P78509-1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3400

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00640

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0312

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.0255

AC:

6376

AN:

250344

Hom.:

106

AF XY:

0.0261

AC XY:

3528

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00567

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.0283

Gnomad SAS exome

AF:

0.0193

Gnomad FIN exome

AF:

0.0387

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0311

AC:

45316

AN:

1458938

Hom.:

764

Cov.:

AF XY:

0.0306

AC XY:

22243

AN XY:

725896

show subpopulations

Gnomad4 AFR exome

AF:

0.00518

Gnomad4 AMR exome

AF:

0.0163

Gnomad4 ASJ exome

AF:

0.0151

Gnomad4 EAS exome

AF:

0.0232

Gnomad4 SAS exome

AF:

0.0193

Gnomad4 FIN exome

AF:

0.0367

Gnomad4 NFE exome

AF:

0.0341

Gnomad4 OTH exome

AF:

0.0275

GnomAD4 genome

AF:

0.0224

AC:

3400

AN:

152104

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1655

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00638

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.0250

Gnomad4 SAS

AF:

0.0159

Gnomad4 FIN

AF:

0.0337

Gnomad4 NFE

AF:

0.0312

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.0290

Hom.:

112

Bravo

AF:

0.0209

TwinsUK

AF:

0.0405

AC:

150

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0328

AC:

282

ExAC

AF:

0.0249

AC:

3021

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0295

EpiControl

AF:

0.0298

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2013	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RELN: BS1, BS2 -

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

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.029

D;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.33

MutPred

0.37

Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);

MPC

0.73

ClinPred

0.0090

GERP RS

5.6

Varity_R

0.41

gMVP

0.75

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