rs115640958

Variant names:

• chr7-103515218-C-T
• rs115640958
• NM_005045.4:c.8086G>A

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.8086G>A​(p.Ala2696Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,614,142 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.74
• Publications: 3 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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038847327).
• BP6: Variant 7-103515218-C-T is Benign according to our data. Variant chr7-103515218-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1708/152250) while in subpopulation AFR AF = 0.0392 (1626/41528). AF 95% confidence interval is 0.0376. There are 28 homozygotes in GnomAd4. There are 819 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.8086G>A	p.Ala2696Thr	missense	Exon 50 of 65	NP_005036.2
	RELN	NM_173054.3		c.8086G>A	p.Ala2696Thr	missense	Exon 50 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.8086G>A	p.Ala2696Thr	missense	Exon 50 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.8086G>A	p.Ala2696Thr	missense	Exon 50 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1704 AN: 152132 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

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: 0.0000588

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00282 AC: 709 AN: 251220 AF XY: 0.00201

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00112 AC: 1639 AN: 1461892 Hom.: 24 Cov.: 31 AF XY: 0.000967 AC XY: 703 AN XY: 727248

African (AFR) AF: 0.0410 AC: 1374 AN: 33480

American (AMR) AF: 0.00199 AC: 89 AN: 44724

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112012

Other (OTH) AF: 0.00232 AC: 140 AN: 60396

GnomAD4 genome AF: 0.0112 AC: 1708 AN: 152250 Hom.: 28 Cov.: 32 AF XY: 0.0110 AC XY: 819 AN XY: 74438

African (AFR) AF: 0.0392 AC: 1626 AN: 41528

American (AMR) AF: 0.00366 AC: 56 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00469 Hom.: 27

Bravo AF: 0.0127

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00364 AC: 442

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;CN030884:Epilepsy, familial temporal lobe, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.026
Sift	Benign	0.10	T
Sift4G	Benign	0.31	T
Polyphen		0.51	P
Vest4		0.65
MVP		0.27
MPC		0.32
ClinPred		0.0076	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.075
gMVP		0.31
Mutation Taster		=98/2	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: rs115640958; hg19: chr7-103155665;