rs362746

Variant names:

• chr7-103539148-A-G
• rs362746
• NM_005045.4:c.7110T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005045.4(RELN):​c.7110T>C​(p.Val2370Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,614,178 control chromosomes in the GnomAD database, including 1,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (152 hom., cov: 33)
  • Exomes 𝑓: 0.029 (1515 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0270
• Publications: 14 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: PanelApp Australia, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-103539148-A-G is Benign according to our data. Variant chr7-103539148-A-G is described in ClinVar as Benign. ClinVar VariationId is 95228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 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.7110T>C	p.Val2370Val	synonymous	Exon 45 of 65	NP_005036.2
	RELN	NM_173054.3		c.7110T>C	p.Val2370Val	synonymous	Exon 45 of 64	NP_774959.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.7110T>C	p.Val2370Val	synonymous	Exon 45 of 65	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.7110T>C	p.Val2370Val	synonymous	Exon 45 of 65	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.7110T>C	p.Val2370Val	synonymous	Exon 45 of 64	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3568 AN: 152182 Hom.: 153 Cov.: 33

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0382 AC: 9603 AN: 251368 AF XY: 0.0399

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0293 AC: 42889 AN: 1461876 Hom.: 1515 Cov.: 32 AF XY: 0.0308 AC XY: 22364 AN XY: 727242

African (AFR) AF: 0.00367 AC: 123 AN: 33478

American (AMR) AF: 0.00519 AC: 232 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 278 AN: 26136

East Asian (EAS) AF: 0.203 AC: 8041 AN: 39696

South Asian (SAS) AF: 0.0710 AC: 6128 AN: 86258

European-Finnish (FIN) AF: 0.0187 AC: 1001 AN: 53418

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 25066 AN: 1112002

Other (OTH) AF: 0.0326 AC: 1969 AN: 60396

GnomAD4 genome AF: 0.0234 AC: 3564 AN: 152302 Hom.: 152 Cov.: 33 AF XY: 0.0244 AC XY: 1819 AN XY: 74474

African (AFR) AF: 0.00469 AC: 195 AN: 41566

American (AMR) AF: 0.00745 AC: 114 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1027 AN: 5182

South Asian (SAS) AF: 0.0790 AC: 381 AN: 4824

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0231 AC: 1571 AN: 68022

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0255 Hom.: 174

Bravo AF: 0.0218

Asia WGS AF: 0.130 AC: 450 AN: 3478

EpiCase AF: 0.0209

EpiControl AF: 0.0178

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.0
DANN	Benign	0.57
PhyloP100		0.027
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs362746; hg19: chr7-103179595; COSMIC: COSV58991889;