rs362698

Variant names:

• chr7-103636845-T-C
• rs362698
• NM_005045.4:c.2070-377A>G

Variant summary

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

The NM_005045.4(RELN):​c.2070-377A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,238 control chromosomes in the GnomAD database, including 1,881 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 0.15 (1881 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.527
• 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• 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 (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.2070-377A>G		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.2070-377A>G		intron	N/A	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.2070-377A>G		intron	N/A	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.2070-377A>G		intron	N/A	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.2070-377A>G		intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22715 AN: 152120 Hom.: 1879 Cov.: 32

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.152

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

GnomAD4 genome AF: 0.149 AC: 22722 AN: 152238 Hom.: 1881 Cov.: 32 AF XY: 0.153 AC XY: 11410 AN XY: 74434

African (AFR) AF: 0.0931 AC: 3870 AN: 41562

American (AMR) AF: 0.174 AC: 2663 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1527 AN: 5178

South Asian (SAS) AF: 0.207 AC: 999 AN: 4820

European-Finnish (FIN) AF: 0.192 AC: 2032 AN: 10596

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10665 AN: 68002

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.156 Hom.: 6835

Bravo AF: 0.147

Asia WGS AF: 0.250 AC: 867 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.47
DANN	Benign	0.52
PhyloP100		-0.53
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: rs362698; hg19: chr7-103277292;