rs262375

Variant names:

• chr7-103812610-G-A
• rs262375
• NM_005045.4:c.473+20927C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005045.4(RELN):​c.473+20927C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 152,056 control chromosomes in the GnomAD database, including 42,104 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42104 hom., cov: 31)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351
• Publications: 4 publications found

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]

RELN Gene-Disease associations (from GenCC):

• lissencephaly with cerebellar hypoplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Norman-Roberts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• familial temporal lobe epilepsy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ankylosing spondylitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.473+20927C>T		intron_variant	Intron 3 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.473+20927C>T		intron_variant	Intron 3 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.473+20927C>T		intron_variant	Intron 3 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112433 AN: 151938 Hom.: 42076 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.866

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.735

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.740 AC: 112511 AN: 152056 Hom.: 42104 Cov.: 31 AF XY: 0.742 AC XY: 55161 AN XY: 74316

African (AFR) AF: 0.629 AC: 26060 AN: 41432

American (AMR) AF: 0.722 AC: 11022 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2826 AN: 3468

East Asian (EAS) AF: 0.637 AC: 3293 AN: 5168

South Asian (SAS) AF: 0.744 AC: 3581 AN: 4816

European-Finnish (FIN) AF: 0.874 AC: 9254 AN: 10594

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.793 AC: 53892 AN: 67998

Other (OTH) AF: 0.738 AC: 1553 AN: 2104

Alfa AF: 0.771 Hom.: 76887

Bravo AF: 0.724

Asia WGS AF: 0.703 AC: 2443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.19
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs262375; hg19: chr7-103453057; COSMIC: COSV107407860;