rs2229860

Variant names:

• chr7-103565380-G-C
• rs2229860
• NM_005045.4:c.5108C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005045.4(RELN):​c.5108C>G​(p.Pro1703Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,614,054 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (19 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 9.26
• Publications: 22 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]

RELN Gene-Disease associations (from GenCC):

• lissencephaly with cerebellar hypoplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Norman-Roberts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• familial temporal lobe epilepsy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ankylosing spondylitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023003519).
• BP6: Variant 7-103565380-G-C is Benign according to our data. Variant chr7-103565380-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130125.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00351 (535/152250) while in subpopulation NFE AF = 0.00568 (386/68008). AF 95% confidence interval is 0.00521. There are 0 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.5108C>G	p.Pro1703Arg	missense	Exon 34 of 65	NP_005036.2
	RELN	NM_173054.3		c.5108C>G	p.Pro1703Arg	missense	Exon 34 of 64	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.5108C>G	p.Pro1703Arg	missense	Exon 34 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.5108C>G	p.Pro1703Arg	missense	Exon 34 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.5108C>G	p.Pro1703Arg	missense	Exon 34 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00568

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00325 AC: 817 AN: 251316 AF XY: 0.00331

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.00474

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00455 AC: 6656 AN: 1461804 Hom.: 19 Cov.: 33 AF XY: 0.00454 AC XY: 3301 AN XY: 727206

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.00183 AC: 82 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86256

European-Finnish (FIN) AF: 0.00680 AC: 363 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00524 AC: 5827 AN: 1111962

Other (OTH) AF: 0.00389 AC: 235 AN: 60392

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74428

African (AFR) AF: 0.000746 AC: 31 AN: 41550

American (AMR) AF: 0.00288 AC: 44 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00568 AC: 386 AN: 68008

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00526 Hom.: 0

Bravo AF: 0.00301

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00330 AC: 401

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	-	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.55
MPC		0.71
ClinPred		0.030	T
GERP RS		6.0
Varity_R		0.46
gMVP		0.82
Mutation Taster		=96/4	polymorphism

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: rs2229860; hg19: chr7-103205827;