rs794727997

Positions:

• chr7-103503158-C-A
• chr7-103503158-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_005045.4(RELN):​c.8347G>T​(p.Gly2783Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.32

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 7-103503158-C-A is Pathogenic according to our data. Variant chr7-103503158-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 199433.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.8347G>T	p.Gly2783Cys	missense_variant	52/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.8347G>T	p.Gly2783Cys	missense_variant	52/64		NP_774959.1
SLC26A5-AS1	NR_110141.1	n.1366-1246C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.8347G>T	p.Gly2783Cys	missense_variant	52/65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial temporal lobe epilepsy 7 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 04, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.74		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.64
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs794727997; hg19: chr7-103143605;