rs56342240

Positions:

• chr7-103594381-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005045.4(RELN):​c.3651C>G​(p.Ile1217Met) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,996 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (16 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 6.15

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014514536).
• BP6: Variant 7-103594381-G-C is Benign according to our data. Variant chr7-103594381-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95218.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=3}. Variant chr7-103594381-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (420/152284) while in subpopulation NFE AF= 0.00528 (359/68022). AF 95% confidence interval is 0.00483. There are 1 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.3651C>G	p.Ile1217Met	missense_variant	26/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.3651C>G	p.Ile1217Met	missense_variant	26/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.3651C>G	p.Ile1217Met	missense_variant	26/65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00247 AC: 619 AN: 251098 Hom.: 2 AF XY: 0.00240 AC XY: 325 AN XY: 135674

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00474

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00406 AC: 5931 AN: 1461712 Hom.: 16 Cov.: 32 AF XY: 0.00396 AC XY: 2879 AN XY: 727158

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00500

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74468

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00528

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00420 Hom.: 0

Bravo AF: 0.00266

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00268 AC: 326

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00387

EpiControl AF: 0.00368

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RELN: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	This variant is associated with the following publications: (PMID: 25648840, 26302956) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 07, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2017	- -

Norman-Roberts syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 09, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.66	P;P;.
Vest4		0.89
MVP		0.13
MPC		0.46
ClinPred		0.027	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs56342240; hg19: chr7-103234828;