rs2229864

chr7-103515258-A-G

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.8046T>C(p.His2682=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,613,780 control chromosomes in the GnomAD database, including 143,927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21989 hom., cov: 32)
  • Exomes 𝑓: 0.39 (121938 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.43

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=-0.79).
• BP6: Variant 7-103515258-A-G is Benign according to our data. Variant chr7-103515258-A-G is described in ClinVar as [Benign]. Clinvar id is 95230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103515258-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.8046T>C	p.His2682=	synonymous_variant	50/65	ENST00000428762.6
RELN	NM_173054.3	c.8046T>C	p.His2682=	synonymous_variant	50/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.8046T>C	p.His2682=	synonymous_variant	50/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76497 AN: 151894 Hom.: 21941 Cov.: 32

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.463 AC: 116373 AN: 251162 Hom.: 30209 AF XY: 0.461 AC XY: 62563 AN XY: 135758

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.805

Gnomad SAS exome AF: 0.618

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.391 AC: 571285 AN: 1461768 Hom.: 121938 Cov.: 55 AF XY: 0.396 AC XY: 288107 AN XY: 727174

Gnomad4 AFR exome AF: 0.773

Gnomad4 AMR exome AF: 0.450

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.796

Gnomad4 SAS exome AF: 0.608

Gnomad4 FIN exome AF: 0.354

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.504 AC: 76615 AN: 152012 Hom.: 21989 Cov.: 32 AF XY: 0.507 AC XY: 37704 AN XY: 74320

Gnomad4 AFR AF: 0.762

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.642

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.485

Alfa AF: 0.387 Hom.: 16089

Bravo AF: 0.517

Asia WGS AF: 0.746 AC: 2595 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.11
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs2229864; hg19: chr7-103155705; COSMIC: COSV100632618; COSMIC: COSV100632618;