rs2075043

chr7-103540425-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.6702T>C(p.Cys2234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,613,844 control chromosomes in the GnomAD database, including 3,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (428 hom., cov: 32)
  • Exomes 𝑓: 0.054 (3103 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.95

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=-0.6).
• BP6: Variant 7-103540425-A-G is Benign according to our data. Variant chr7-103540425-A-G is described in ClinVar as [Benign]. Clinvar id is 95227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103540425-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.6702T>C	p.Cys2234=	synonymous_variant	44/65	ENST00000428762.6
RELN	NM_173054.3	c.6702T>C	p.Cys2234=	synonymous_variant	44/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.6702T>C	p.Cys2234=	synonymous_variant	44/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0621 AC: 9445 AN: 152106 Hom.: 429 Cov.: 32

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.0826

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0637

GnomAD3 exomes AF: 0.0787 AC: 19759 AN: 251062 Hom.: 1192 AF XY: 0.0763 AC XY: 10355 AN XY: 135726

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.0735

Gnomad EAS exome AF: 0.246

Gnomad SAS exome AF: 0.0842

Gnomad FIN exome AF: 0.0933

Gnomad NFE exome AF: 0.0440

Gnomad OTH exome AF: 0.0649

GnomAD4 exome AF: 0.0541 AC: 79103 AN: 1461620 Hom.: 3103 Cov.: 32 AF XY: 0.0543 AC XY: 39458 AN XY: 727094

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0767

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.0817

Gnomad4 FIN exome AF: 0.0969

Gnomad4 NFE exome AF: 0.0420

Gnomad4 OTH exome AF: 0.0632

GnomAD4 genome AF: 0.0622 AC: 9464 AN: 152224 Hom.: 428 Cov.: 32 AF XY: 0.0652 AC XY: 4851 AN XY: 74436

Gnomad4 AFR AF: 0.0510

Gnomad4 AMR AF: 0.0864

Gnomad4 ASJ AF: 0.0692

Gnomad4 EAS AF: 0.250

Gnomad4 SAS AF: 0.0837

Gnomad4 FIN AF: 0.0925

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0654

Alfa AF: 0.0522 Hom.: 90

Bravo AF: 0.0610

Asia WGS AF: 0.145 AC: 504 AN: 3478

EpiCase AF: 0.0433

EpiControl AF: 0.0415

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Feb 27, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2012	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.0
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2075043; hg19: chr7-103180872; COSMIC: COSV59000954; COSMIC: COSV59000954;