NM_005045.4:c.2989C>G

Variant names:

• chr7-103610714-G-C
• rs362691
• NM_005045.4:c.2989C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.2989C>G​(p.Leu997Val) variant causes a missense change. The variant allele was found at a frequency of 0.11 in 1,581,198 control chromosomes in the GnomAD database, including 10,098 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L997F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.11 (918 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9180 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.11
• Publications: 67 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014434159).
• BP6: Variant 7-103610714-G-C is Benign according to our data. Variant chr7-103610714-G-C is described in ClinVar as Benign. ClinVar VariationId is 130119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.159 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.2989C>G	p.Leu997Val	missense	Exon 22 of 65	NP_005036.2
	RELN	NM_173054.3		c.2989C>G	p.Leu997Val	missense	Exon 22 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.2989C>G	p.Leu997Val	missense	Exon 22 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.2989C>G	p.Leu997Val	missense	Exon 22 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.2989C>G	p.Leu997Val	missense	Exon 22 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16029 AN: 152044 Hom.: 921 Cov.: 32

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.116 AC: 28983 AN: 250826 AF XY: 0.118

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0940

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.0973

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.111 AC: 158211 AN: 1429036 Hom.: 9180 Cov.: 28 AF XY: 0.112 AC XY: 80087 AN XY: 712990

African (AFR) AF: 0.0825 AC: 2701 AN: 32730

American (AMR) AF: 0.111 AC: 4953 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 2369 AN: 25938

East Asian (EAS) AF: 0.109 AC: 4309 AN: 39510

South Asian (SAS) AF: 0.157 AC: 13392 AN: 85522

European-Finnish (FIN) AF: 0.0985 AC: 5233 AN: 53134

Middle Eastern (MID) AF: 0.0962 AC: 549 AN: 5704

European-Non Finnish (NFE) AF: 0.109 AC: 117894 AN: 1082498

Other (OTH) AF: 0.115 AC: 6811 AN: 59322

GnomAD4 genome AF: 0.105 AC: 16025 AN: 152162 Hom.: 918 Cov.: 32 AF XY: 0.105 AC XY: 7847 AN XY: 74398

African (AFR) AF: 0.0840 AC: 3488 AN: 41540

American (AMR) AF: 0.119 AC: 1822 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 294 AN: 3468

East Asian (EAS) AF: 0.129 AC: 667 AN: 5168

South Asian (SAS) AF: 0.168 AC: 812 AN: 4820

European-Finnish (FIN) AF: 0.0993 AC: 1051 AN: 10586

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7567 AN: 67980

Other (OTH) AF: 0.111 AC: 234 AN: 2108

Alfa AF: 0.0814 Hom.: 229

Bravo AF: 0.104

TwinsUK AF: 0.108 AC: 399

ALSPAC AF: 0.114 AC: 439

ESP6500AA AF: 0.0833 AC: 367

ESP6500EA AF: 0.104 AC: 893

ExAC AF: 0.116 AC: 14120

Asia WGS AF: 0.170 AC: 588 AN: 3476

EpiCase AF: 0.104

EpiControl AF: 0.105

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	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	Benign	0.084
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.048
Sift	Benign	0.59	T
Sift4G	Benign	0.36	T
Polyphen		0.19	B
Vest4		0.059
MPC		0.17
ClinPred		0.010	T
GERP RS		4.4
Varity_R		0.065
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs362691; hg19: chr7-103251161; COSMIC: COSV58986400;