chr7-103515258-A-G

Variant names:

• chr7-103515258-A-G
• rs2229864
• NM_005045.4:c.8046T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005045.4(RELN):​c.8046T>C​(p.His2682His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,613,780 control chromosomes in the GnomAD database, including 143,927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21989 hom., cov: 32)
  • Exomes 𝑓: 0.39 (121938 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.43
• Publications: 37 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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-103515258-A-G is Benign according to our data. Variant chr7-103515258-A-G is described in ClinVar as Benign. ClinVar VariationId is 95230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 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.8046T>C	p.His2682His	synonymous	Exon 50 of 65	NP_005036.2
	RELN	NM_173054.3		c.8046T>C	p.His2682His	synonymous	Exon 50 of 64	NP_774959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.8046T>C	p.His2682His	synonymous	Exon 50 of 65	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.8046T>C	p.His2682His	synonymous	Exon 50 of 65	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.8046T>C	p.His2682His	synonymous	Exon 50 of 64	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76497 AN: 151894 Hom.: 21941 Cov.: 32

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.480

GnomAD2 exomes AF: 0.463 AC: 116373 AN: 251162 AF XY: 0.461

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.805

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.391 AC: 571285 AN: 1461768 Hom.: 121938 Cov.: 55 AF XY: 0.396 AC XY: 288107 AN XY: 727174

African (AFR) AF: 0.773 AC: 25896 AN: 33480

American (AMR) AF: 0.450 AC: 20099 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 10118 AN: 26136

East Asian (EAS) AF: 0.796 AC: 31613 AN: 39698

South Asian (SAS) AF: 0.608 AC: 52481 AN: 86256

European-Finnish (FIN) AF: 0.354 AC: 18882 AN: 53410

Middle Eastern (MID) AF: 0.421 AC: 2426 AN: 5768

European-Non Finnish (NFE) AF: 0.345 AC: 383690 AN: 1111940

Other (OTH) AF: 0.432 AC: 26080 AN: 60390

GnomAD4 genome AF: 0.504 AC: 76615 AN: 152012 Hom.: 21989 Cov.: 32 AF XY: 0.507 AC XY: 37704 AN XY: 74320

African (AFR) AF: 0.762 AC: 31581 AN: 41470

American (AMR) AF: 0.457 AC: 6975 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1314 AN: 3470

East Asian (EAS) AF: 0.807 AC: 4154 AN: 5146

South Asian (SAS) AF: 0.642 AC: 3092 AN: 4818

European-Finnish (FIN) AF: 0.354 AC: 3736 AN: 10564

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24320 AN: 67962

Other (OTH) AF: 0.485 AC: 1022 AN: 2108

Alfa AF: 0.406 Hom.: 28442

Bravo AF: 0.517

Asia WGS AF: 0.746 AC: 2595 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jul 03, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Norman-Roberts syndrome Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.11
DANN	Benign	0.55
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs2229864; hg19: chr7-103155705; COSMIC: COSV100632618; COSMIC: COSV100632618;