rs147657490

chr7-103565393-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_005045.4(RELN):c.5095G>A(p.Glu1699Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,916 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.05

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0959872).
• BP6: Variant 7-103565393-C-T is Benign according to our data. Variant chr7-103565393-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130124.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000316 (48/152114) while in subpopulation NFE AF= 0.000456 (31/68014). AF 95% confidence interval is 0.00033. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.5095G>A	p.Glu1699Lys	missense_variant	34/65	ENST00000428762.6
RELN	NM_173054.3	c.5095G>A	p.Glu1699Lys	missense_variant	34/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.5095G>A	p.Glu1699Lys	missense_variant	34/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251282 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135808

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000451 AC: 660 AN: 1461802 Hom.: 1 Cov.: 33 AF XY: 0.000429 AC XY: 312 AN XY: 727200

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152114 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74302

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RELN: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 23, 2014	- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.038
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.38
MVP		0.25
MPC		0.20
ClinPred		0.024	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.55

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: rs147657490; hg19: chr7-103205840; COSMIC: COSV100633831;