rs79499902

chr7-103561880-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):c.5284G>A(p.Val1762Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00413 in 1,565,482 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (32 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 4.57

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.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073706806).
• BP6: Variant 7-103561880-C-T is Benign according to our data. Variant chr7-103561880-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103561880-C-T is described in Lovd as [Benign]. Variant chr7-103561880-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1480/146512) while in subpopulation AFR AF= 0.0274 (1093/39888). AF 95% confidence interval is 0.0261. There are 16 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.5284G>A	p.Val1762Ile	missense_variant	35/65	ENST00000428762.6
RELN	NM_173054.3	c.5284G>A	p.Val1762Ile	missense_variant	35/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.5284G>A	p.Val1762Ile	missense_variant	35/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1477 AN: 146398 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00646

Gnomad ASJ AF: 0.00958

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00206

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00336

Gnomad OTH AF: 0.0113

GnomAD3 exomes AF: 0.00475 AC: 1192 AN: 251180 Hom.: 11 AF XY: 0.00440 AC XY: 598 AN XY: 135762

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00374

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00352 AC: 4989 AN: 1418970 Hom.: 32 Cov.: 34 AF XY: 0.00354 AC XY: 2499 AN XY: 706156

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.000202

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.0101 AC: 1480 AN: 146512 Hom.: 16 Cov.: 30 AF XY: 0.0101 AC XY: 715 AN XY: 70948

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00645

Gnomad4 ASJ AF: 0.00958

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00206

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00336

Gnomad4 OTH AF: 0.0112

Alfa AF: 0.00474 Hom.: 6

Bravo AF: 0.0115

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00516 AC: 626

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2015	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RELN p.Val1762Ile variant was not identified in the literature but was identified in dbSNP (ID: rs79499902), LOVD 3.0 and ClinVar (classified as benign by Prevention Genetics, Genetic Services Laboratory, University of Chicago, GeneDx, EGL Genetic Diagnostics, and Invitae, as likely benign by Athena Diagnostics Inc and Illumina and as pathogenic by Bioinformatics Core, Luxembourg Center for Systems Biomedicine). The variant was identified in control databases in 1463 of 282336 chromosomes (13 homozygous) at a frequency of 0.005182 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 687 of 24876 chromosomes (freq: 0.02762), Ashkenazi Jewish in 116 of 10364 chromosomes (freq: 0.01119), Latino in 138 of 35352 chromosomes (freq: 0.003904), Other in 27 of 7208 chromosomes (freq: 0.003746), European (non-Finnish) in 413 of 128966 chromosomes (freq: 0.003202), South Asian in 78 of 30612 chromosomes (freq: 0.002548), European (Finnish) in 3 of 25064 chromosomes (freq: 0.00012), and East Asian in 1 of 19894 chromosomes (freq: 0.00005). The p.Val1762 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

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

Nov 08, 2021

- -

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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

RELN: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.039
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.062	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.30
MVP		0.068
MPC		0.14
ClinPred		0.012	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.41

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: rs79499902; hg19: chr7-103202327;