chr7-103748638-T-C

Variant names:

• chr7-103748638-T-C
• rs528528
• NM_005045.4:c.656+788A>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.656+788A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 152,058 control chromosomes in the GnomAD database, including 19,202 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 0.50 (19202 hom., cov: 33)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.539 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.656+788A>G		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.656+788A>G		intron	N/A	NP_774959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.656+788A>G		intron	N/A	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.656+788A>G		intron	N/A	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.656+788A>G		intron	N/A	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.500 AC: 76032 AN: 151940 Hom.: 19172 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.525

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

GnomAD4 genome AF: 0.500 AC: 76102 AN: 152058 Hom.: 19202 Cov.: 33 AF XY: 0.496 AC XY: 36852 AN XY: 74326

African (AFR) AF: 0.473 AC: 19638 AN: 41490

American (AMR) AF: 0.468 AC: 7148 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1694 AN: 3460

East Asian (EAS) AF: 0.380 AC: 1967 AN: 5176

South Asian (SAS) AF: 0.477 AC: 2304 AN: 4826

European-Finnish (FIN) AF: 0.447 AC: 4716 AN: 10560

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36911 AN: 67952

Other (OTH) AF: 0.521 AC: 1099 AN: 2108

Alfa AF: 0.530 Hom.: 71556

Bravo AF: 0.499

Asia WGS AF: 0.395 AC: 1372 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.65
PhyloP100		0.049
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: rs528528; hg19: chr7-103389085;