rs6943822

Variant names:

• chr7-103958224-T-C
• rs6943822
• NM_005045.4:c.226+30907A>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.226+30907A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 152,052 control chromosomes in the GnomAD database, including 10,116 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 0.36 (10116 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.226+30907A>G		intron_variant	Intron 1 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.226+30907A>G		intron_variant	Intron 1 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.226+30907A>G		intron_variant	Intron 1 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53979 AN: 151934 Hom.: 10114 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.355 AC: 54008 AN: 152052 Hom.: 10116 Cov.: 32 AF XY: 0.350 AC XY: 25991 AN XY: 74330

African (AFR) AF: 0.266 AC: 11013 AN: 41446

American (AMR) AF: 0.350 AC: 5351 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1626 AN: 3470

East Asian (EAS) AF: 0.230 AC: 1185 AN: 5162

South Asian (SAS) AF: 0.145 AC: 700 AN: 4820

European-Finnish (FIN) AF: 0.394 AC: 4163 AN: 10578

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28623 AN: 67982

Other (OTH) AF: 0.393 AC: 831 AN: 2114

Alfa AF: 0.402 Hom.: 53803

Bravo AF: 0.354

Asia WGS AF: 0.188 AC: 655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.42
PhyloP100		0.27
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: rs6943822; hg19: chr7-103598671;