rs41276154

chr7-103652718-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005045.4(RELN):c.1596G>A(p.Gln532=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,612,708 control chromosomes in the GnomAD database, including 866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (157 hom., cov: 32)
  • Exomes 𝑓: 0.028 (709 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.20

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 7-103652718-C-T is Benign according to our data. Variant chr7-103652718-C-T is described in ClinVar as [Benign]. Clinvar id is 95212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103652718-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.1596G>A	p.Gln532=	synonymous_variant	14/65	ENST00000428762.6
RELN	NM_173054.3	c.1596G>A	p.Gln532=	synonymous_variant	14/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.1596G>A	p.Gln532=	synonymous_variant	14/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5854 AN: 151958 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0712

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00893

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0237 AC: 5938 AN: 250726 Hom.: 108 AF XY: 0.0224 AC XY: 3039 AN XY: 135488

Gnomad AFR exome AF: 0.0716

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00853

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0281 AC: 41046 AN: 1460632 Hom.: 709 Cov.: 32 AF XY: 0.0274 AC XY: 19902 AN XY: 726642

Gnomad4 AFR exome AF: 0.0739

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00850

Gnomad4 FIN exome AF: 0.0224

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0385 AC: 5853 AN: 152076 Hom.: 157 Cov.: 32 AF XY: 0.0372 AC XY: 2765 AN XY: 74338

Gnomad4 AFR AF: 0.0710

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00894

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0305

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0334 Hom.: 58

Bravo AF: 0.0404

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0290

EpiControl AF: 0.0252

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Jan 28, 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, 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	-	- -

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 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
BayesDel_noAF	Benign	-0.37
Cadd	Benign	7.9
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41276154; hg19: chr7-103293165; COSMIC: COSV59018703;