rs386542726

chr7-103500904-G-Achr7-103500904-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005045.4(RELN):c.8508C>T(p.Phe2836=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0467 in 1,613,868 control chromosomes in the GnomAD database, including 1,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (137 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1795 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.54

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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 7-103500904-G-A is Benign according to our data. Variant chr7-103500904-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103500904-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.8508C>T	p.Phe2836=	synonymous_variant	53/65	ENST00000428762.6
SLC26A5-AS1	NR_110141.1	n.1366-3500G>A		intron_variant, non_coding_transcript_variant
RELN	NM_173054.3	c.8508C>T	p.Phe2836=	synonymous_variant	53/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.8508C>T	p.Phe2836=	synonymous_variant	53/65	5	NM_005045.4	P5
SLC26A5-AS1	ENST00000422488.1	n.1366-3500G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5595 AN: 152126 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0539

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0361 AC: 9066 AN: 251314 Hom.: 213 AF XY: 0.0369 AC XY: 5006 AN XY: 135834

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0492

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.0486

GnomAD4 exome AF: 0.0477 AC: 69699 AN: 1461624 Hom.: 1795 Cov.: 32 AF XY: 0.0466 AC XY: 33865 AN XY: 727120

Gnomad4 AFR exome AF: 0.00789

Gnomad4 AMR exome AF: 0.0288

Gnomad4 ASJ exome AF: 0.0367

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.0514

Gnomad4 NFE exome AF: 0.0545

Gnomad4 OTH exome AF: 0.0423

GnomAD4 genome AF: 0.0368 AC: 5595 AN: 152244 Hom.: 137 Cov.: 32 AF XY: 0.0367 AC XY: 2732 AN XY: 74438

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0487

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.0449

Gnomad4 NFE AF: 0.0539

Gnomad4 OTH AF: 0.0365

Alfa AF: 0.0454 Hom.: 84

Bravo AF: 0.0350

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0502

EpiControl AF: 0.0493

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

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 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	9.2
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2229862; hg19: chr7-103141351; COSMIC: COSV59033924;