rs2072403

Positions:

• chr7-103651777-T-C

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.1776A>G​(p.Glu592Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,610,778 control chromosomes in the GnomAD database, including 3,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (951 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2924 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.59

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=-0.57).
• BP6: Variant 7-103651777-T-C is Benign according to our data. Variant chr7-103651777-T-C is described in ClinVar as [Benign]. Clinvar id is 130115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103651777-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.1776A>G	p.Glu592Glu	synonymous_variant	15/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.1776A>G	p.Glu592Glu	synonymous_variant	15/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.1776A>G	p.Glu592Glu	synonymous_variant	15/65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14227 AN: 151542 Hom.: 944 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0439

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0795

GnomAD3 exomes AF: 0.0752 AC: 18762 AN: 249660 Hom.: 978 AF XY: 0.0691 AC XY: 9330 AN XY: 134978

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.0409

Gnomad FIN exome AF: 0.0765

Gnomad NFE exome AF: 0.0474

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0557 AC: 81210 AN: 1459118 Hom.: 2924 Cov.: 31 AF XY: 0.0545 AC XY: 39591 AN XY: 725888

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0422

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0728

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0592

GnomAD4 genome AF: 0.0941 AC: 14264 AN: 151660 Hom.: 951 Cov.: 32 AF XY: 0.0945 AC XY: 7001 AN XY: 74104

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0767

Gnomad4 ASJ AF: 0.0439

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.0362

Gnomad4 FIN AF: 0.0814

Gnomad4 NFE AF: 0.0480

Gnomad4 OTH AF: 0.0801

Alfa AF: 0.0616 Hom.: 218

Bravo AF: 0.100

Asia WGS AF: 0.0920 AC: 319 AN: 3476

EpiCase AF: 0.0407

EpiControl AF: 0.0422

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome Benign:2

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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.1
DANN	Benign	0.47

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: rs2072403; hg19: chr7-103292224; COSMIC: COSV58989682;