rs2711885

Positions:

• chr7-103498070-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.8843+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,613,976 control chromosomes in the GnomAD database, including 786,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74597 hom., cov: 32)
  • Exomes 𝑓: 0.99 (711416 hom.)
• Consequence: RELN NM_005045.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001489
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.100

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]

SLC26A5-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-103498070-C-G is Benign according to our data. Variant chr7-103498070-C-G is described in ClinVar as [Benign]. Clinvar id is 95234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103498070-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.8843+7G>C		splice_region_variant, intron_variant		ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.8843+7G>C		splice_region_variant, intron_variant			NP_774959.1
SLC26A5-AS1	NR_110141.1	n.1366-6334C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.8843+7G>C		splice_region_variant, intron_variant		5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.990 AC: 150621 AN: 152198 Hom.: 74537 Cov.: 32

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 0.975

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.992

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.986

Gnomad OTH AF: 0.988

GnomAD3 exomes AF: 0.987 AC: 247858 AN: 251068 Hom.: 122367 AF XY: 0.987 AC XY: 133917 AN XY: 135668

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 0.978

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.990

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.985

Gnomad OTH exome AF: 0.982

GnomAD4 exome AF: 0.987 AC: 1442059 AN: 1461660 Hom.: 711416 Cov.: 43 AF XY: 0.987 AC XY: 717415 AN XY: 727152

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.995

Gnomad4 ASJ exome AF: 0.978

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.990

Gnomad4 FIN exome AF: 0.971

Gnomad4 NFE exome AF: 0.986

Gnomad4 OTH exome AF: 0.987

GnomAD4 genome AF: 0.990 AC: 150741 AN: 152316 Hom.: 74597 Cov.: 32 AF XY: 0.990 AC XY: 73739 AN XY: 74486

Gnomad4 AFR AF: 0.997

Gnomad4 AMR AF: 0.994

Gnomad4 ASJ AF: 0.975

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.992

Gnomad4 FIN AF: 0.977

Gnomad4 NFE AF: 0.986

Gnomad4 OTH AF: 0.988

Alfa AF: 0.985 Hom.: 23935

Bravo AF: 0.991

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs2711885; hg19: chr7-103138517;