rs79610081

Positions:

• chr7-103551291-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005045.4(RELN):​c.6078C>T​(p.Asn2026=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,611,926 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (6 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.534

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 7-103551291-G-A is Benign according to our data. Variant chr7-103551291-G-A is described in ClinVar as [Benign]. Clinvar id is 212043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103551291-G-A is described in Lovd as [Benign]. Variant chr7-103551291-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.534 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00626 (953/152232) while in subpopulation AFR AF= 0.0213 (886/41526). AF 95% confidence interval is 0.0202. There are 13 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.6078C>T	p.Asn2026=	synonymous_variant	41/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.6078C>T	p.Asn2026=	synonymous_variant	41/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.6078C>T	p.Asn2026=	synonymous_variant	41/65	5	NM_005045.4	ENSP00000392423	P5

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 947 AN: 152114 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00166 AC: 413 AN: 249534 Hom.: 3 AF XY: 0.00115 AC XY: 155 AN XY: 134938

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000587 AC: 857 AN: 1459694 Hom.: 6 Cov.: 31 AF XY: 0.000494 AC XY: 359 AN XY: 726206

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00626 AC: 953 AN: 152232 Hom.: 13 Cov.: 32 AF XY: 0.00584 AC XY: 435 AN XY: 74428

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00331 Hom.: 4

Bravo AF: 0.00750

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 01, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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	-0.61
CADD	Benign	0.59
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79610081; hg19: chr7-103191738;