rs115734214

Variant names:

• chr7-103651665-T-G
• rs115734214
• NM_005045.4:c.1888A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.1888A>C​(p.Ser630Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,611,042 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S630S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (42 hom., cov: 32)
  • Exomes 𝑓: 0.031 (764 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.67
• Publications: 12 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=0.009536654).
• BP6: Variant 7-103651665-T-G is Benign according to our data. Variant chr7-103651665-T-G is described in ClinVar as Benign. ClinVar VariationId is 130116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3400/152104) while in subpopulation NFE AF = 0.0312 (2118/67948). AF 95% confidence interval is 0.0301. There are 42 homozygotes in GnomAd4. There are 1655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.1888A>C	p.Ser630Arg	missense	Exon 15 of 65	NP_005036.2
	RELN	NM_173054.3		c.1888A>C	p.Ser630Arg	missense	Exon 15 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.1888A>C	p.Ser630Arg	missense	Exon 15 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.1888A>C	p.Ser630Arg	missense	Exon 15 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.1888A>C	p.Ser630Arg	missense	Exon 15 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3400 AN: 151986 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0312

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0255 AC: 6376 AN: 250344 AF XY: 0.0261

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.0283

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0310

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0311 AC: 45316 AN: 1458938 Hom.: 764 Cov.: 31 AF XY: 0.0306 AC XY: 22243 AN XY: 725896

African (AFR) AF: 0.00518 AC: 173 AN: 33366

American (AMR) AF: 0.0163 AC: 725 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 393 AN: 26048

East Asian (EAS) AF: 0.0232 AC: 918 AN: 39630

South Asian (SAS) AF: 0.0193 AC: 1660 AN: 86218

European-Finnish (FIN) AF: 0.0367 AC: 1959 AN: 53350

Middle Eastern (MID) AF: 0.00644 AC: 37 AN: 5746

European-Non Finnish (NFE) AF: 0.0341 AC: 37797 AN: 1109824

Other (OTH) AF: 0.0275 AC: 1654 AN: 60220

GnomAD4 genome AF: 0.0224 AC: 3400 AN: 152104 Hom.: 42 Cov.: 32 AF XY: 0.0223 AC XY: 1655 AN XY: 74346

African (AFR) AF: 0.00638 AC: 265 AN: 41538

American (AMR) AF: 0.0230 AC: 350 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3468

East Asian (EAS) AF: 0.0250 AC: 129 AN: 5150

South Asian (SAS) AF: 0.0159 AC: 77 AN: 4828

European-Finnish (FIN) AF: 0.0337 AC: 358 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0312 AC: 2118 AN: 67948

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

Alfa AF: 0.0281 Hom.: 236

Bravo AF: 0.0209

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0343 AC: 132

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0328 AC: 282

ExAC AF: 0.0249 AC: 3021

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0295

EpiControl AF: 0.0298

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (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	0.70
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Uncertain	0.029	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.37		Gain of MoRF binding (P = 0.0242)
MPC		0.73
ClinPred		0.0090	T
GERP RS		5.6
Varity_R		0.41
gMVP		0.75
Mutation Taster		=98/2	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: rs115734214; hg19: chr7-103292112; COSMIC: COSV107408155;