rs115734214

chr7-103651665-T-G

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.1888A>C(p.Ser630Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,611,042 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S630S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (42 hom., cov: 32)
  • Exomes 𝑓: 0.031 (764 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.67

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=0.009536654).
• BP6: Variant 7-103651665-T-G is Benign according to our data. Variant chr7-103651665-T-G is described in ClinVar as [Benign]. Clinvar id is 130116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103651665-T-G is described in Lovd as [Benign]. Variant chr7-103651665-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0224 (3400/152104) while in subpopulation NFE AF= 0.0312 (2118/67948). AF 95% confidence interval is 0.0301. There are 42 homozygotes in gnomad4. There are 1655 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.1888A>C	p.Ser630Arg	missense_variant	15/65	ENST00000428762.6
RELN	NM_173054.3	c.1888A>C	p.Ser630Arg	missense_variant	15/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.1888A>C	p.Ser630Arg	missense_variant	15/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3400 AN: 151986 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0312

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0255 AC: 6376 AN: 250344 Hom.: 106 AF XY: 0.0261 AC XY: 3528 AN XY: 135300

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.0283

Gnomad SAS exome AF: 0.0193

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0310

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0311 AC: 45316 AN: 1458938 Hom.: 764 Cov.: 31 AF XY: 0.0306 AC XY: 22243 AN XY: 725896

Gnomad4 AFR exome AF: 0.00518

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0367

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0224 AC: 3400 AN: 152104 Hom.: 42 Cov.: 32 AF XY: 0.0223 AC XY: 1655 AN XY: 74346

Gnomad4 AFR AF: 0.00638

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.0250

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.0312

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0290 Hom.: 112

Bravo AF: 0.0209

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0343 AC: 132

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0328 AC: 282

ExAC AF: 0.0249 AC: 3021

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0295

EpiControl AF: 0.0298

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2013	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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RELN: BS1, BS2 -

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
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0095	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.029	D;D;D
Sift4G	Benign	0.15	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.33
MutPred		0.37		Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);Gain of MoRF binding (P = 0.0242);
MPC		0.73
ClinPred		0.0090	T
GERP RS		5.6
Varity_R		0.41
gMVP		0.75

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: rs115734214; hg19: chr7-103292112;