rs114344654

Variant names:

• chr7-103539144-C-T
• rs114344654
• NM_005045.4:c.7114G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005045.4(RELN):​c.7114G>A​(p.Val2372Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,614,198 control chromosomes in the GnomAD database, including 2 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 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.95
• Publications: 7 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

LOC105375435 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07313931).
• BP6: Variant 7-103539144-C-T is Benign according to our data. Variant chr7-103539144-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130140.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000433 (66/152316) while in subpopulation AFR AF = 0.00106 (44/41572). AF 95% confidence interval is 0.000809. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.7114G>A	p.Val2372Met	missense	Exon 45 of 65	NP_005036.2
	RELN	NM_173054.3		c.7114G>A	p.Val2372Met	missense	Exon 45 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.7114G>A	p.Val2372Met	missense	Exon 45 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.7114G>A	p.Val2372Met	missense	Exon 45 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.7114G>A	p.Val2372Met	missense	Exon 45 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000207 AC: 52 AN: 251352 AF XY: 0.000213

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000218 AC: 319 AN: 1461882 Hom.: 2 Cov.: 31 AF XY: 0.000221 AC XY: 161 AN XY: 727240

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000226 AC: 251 AN: 1112012

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74466

African (AFR) AF: 0.00106 AC: 44 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.64
MPC		1.9
ClinPred		0.032	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.56
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114344654; hg19: chr7-103179591; COSMIC: COSV58992534;