rs150236371

chr7-103523443-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005045.4(RELN):c.7438G>A(p.Gly2480Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00303 in 1,614,086 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (5 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 4.75

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.019006014).
• BP6: Variant 7-103523443-C-T is Benign according to our data. Variant chr7-103523443-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95229.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3, Likely_benign=4}. Variant chr7-103523443-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00231 (351/152234) while in subpopulation NFE AF= 0.00341 (232/68034). AF 95% confidence interval is 0.00305. There are 2 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.7438G>A	p.Gly2480Ser	missense_variant	47/65	ENST00000428762.6
RELN	NM_173054.3	c.7438G>A	p.Gly2480Ser	missense_variant	47/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.7438G>A	p.Gly2480Ser	missense_variant	47/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00257 AC: 647 AN: 251476 Hom.: 0 AF XY: 0.00255 AC XY: 347 AN XY: 135912

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00310 AC: 4534 AN: 1461852 Hom.: 5 Cov.: 31 AF XY: 0.00314 AC XY: 2285 AN XY: 727232

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00957

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00277

Gnomad4 FIN exome AF: 0.00294

Gnomad4 NFE exome AF: 0.00325

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00231 AC: 351 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74426

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00196

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	This variant is associated with the following publications: (PMID: 24828792, 14515139, 30949922) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RELN: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 11, 2016	- -

Norman-Roberts syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.25	T;T;T
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.26	B;D;.
Vest4		0.43
MVP		0.71
MPC		1.9
ClinPred		0.019	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.74

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: rs150236371; hg19: chr7-103163890; COSMIC: COSV58989457; COSMIC: COSV58989457;