rs114019779

Positions:

• chr7-103551285-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005045.4(RELN):​c.6084C>T​(p.Gly2028=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,613,178 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (34 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.357

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=-0.64).
• BP6: Variant 7-103551285-G-A is Benign according to our data. Variant chr7-103551285-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103551285-G-A is described in Lovd as [Benign]. Variant chr7-103551285-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.357 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00489 (745/152264) while in subpopulation NFE AF= 0.00756 (514/68026). AF 95% confidence interval is 0.00702. There are 8 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.6084C>T	p.Gly2028=	synonymous_variant	41/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.6084C>T	p.Gly2028=	synonymous_variant	41/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.6084C>T	p.Gly2028=	synonymous_variant	41/65	5	NM_005045.4	ENSP00000392423	P5

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 745 AN: 152146 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00756

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00452 AC: 1132 AN: 250248 Hom.: 4 AF XY: 0.00445 AC XY: 602 AN XY: 135294

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00834

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00564 AC: 8241 AN: 1460914 Hom.: 34 Cov.: 32 AF XY: 0.00543 AC XY: 3947 AN XY: 726752

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00875

Gnomad4 NFE exome AF: 0.00650

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152264 Hom.: 8 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74448

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.00756

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00574 Hom.: 1

Bravo AF: 0.00442

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00683

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RELN: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Norman-Roberts syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 13, 2021

- -

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	-0.64
CADD	Benign	0.16
DANN	Benign	0.50

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: rs114019779; hg19: chr7-103191732;