rs2075038

Positions:

• chr7-103522160-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005045.4(RELN):​c.7530C>T​(p.Pro2510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,613,916 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (158 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1987 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.51

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-103522160-G-A is Benign according to our data. Variant chr7-103522160-G-A is described in ClinVar as [Benign]. Clinvar id is 130141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103522160-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.7530C>T	p.Pro2510=	synonymous_variant	48/65	ENST00000428762.6
RELN	NM_173054.3	c.7530C>T	p.Pro2510=	synonymous_variant	48/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.7530C>T	p.Pro2510=	synonymous_variant	48/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5770 AN: 152008 Hom.: 159 Cov.: 31

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0222

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0492

GnomAD3 exomes AF: 0.0534 AC: 13431 AN: 251446 Hom.: 578 AF XY: 0.0576 AC XY: 7828 AN XY: 135900

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.0726

Gnomad ASJ exome AF: 0.0617

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0559

GnomAD4 exome AF: 0.0424 AC: 61968 AN: 1461790 Hom.: 1987 Cov.: 32 AF XY: 0.0456 AC XY: 33130 AN XY: 727192

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.0711

Gnomad4 ASJ exome AF: 0.0624

Gnomad4 EAS exome AF: 0.0373

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0488

GnomAD4 genome AF: 0.0381 AC: 5791 AN: 152126 Hom.: 158 Cov.: 31 AF XY: 0.0392 AC XY: 2917 AN XY: 74374

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.0476

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0239

Gnomad4 NFE AF: 0.0356

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0383 Hom.: 71

Bravo AF: 0.0369

Asia WGS AF: 0.0980 AC: 339 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0373

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 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
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.12
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2075038; hg19: chr7-103162607; COSMIC: COSV59008588; COSMIC: COSV59008588;