chr7-103522056-G-A

Position:

chr7-103522056-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS1_Supporting

The NM_005045.4(RELN):c.7634C>T(p.Ala2545Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2545A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 9.47

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:

RELN (HGNC:):

RELN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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=0.27547157).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000145 (22/152158) while in subpopulation NFE AF= 0.000206 (14/68000). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4 linkuse as main transcript	c.7634C>T	p.Ala2545Val	missense_variant	48/65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 linkuse as main transcript	c.7634C>T	p.Ala2545Val	missense_variant	48/64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.7634C>T	p.Ala2545Val	missense_variant	48/65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000215

AC:

AN:

251478

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000341

AC:

498

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

240

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000413

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000145

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000271

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster yielded discordant predictions regarding whether this amino acid change is damaging to the protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2023	Reported previously in an individual with autism spectrum disorder; however, a missense variant in another gene was also identified in this individual and no further clinical information was provided (Varga et al., 2017); Reported previously in an individual with autism spectrum disorder who had a second RELN variant on the opposite chromosome (in trans) (M Sanchez-Sanchez et al., 2018); however we consider the second RELN variant identified to be benign; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29969175, 28677532, 34426522, 32060413, 31623367, 35668055) -

Norman-Roberts syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 10, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2020	- -

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

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2021

Unlikely to be causative of RELN-related lateral temporal epilepsy (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.29

Sift

Benign

0.26

T;T;T

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.0060

B;D;.

Vest4

0.77

MVP

0.38

MPC

0.98

ClinPred

0.22

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.64

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