chr7-103635498-G-T

Variant names:

• chr7-103635498-G-T
• rs794727996
• NM_005045.4:c.2392C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000428762.6(RELN):​c.2392C>A​(p.His798Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RELN ENST00000428762.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.01
• 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]

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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-103635498-G-T is Pathogenic according to our data. Variant chr7-103635498-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 199432.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000428762.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.2392C>A	p.His798Asn	missense	Exon 19 of 65	NP_005036.2
	RELN	NM_173054.3		c.2392C>A	p.His798Asn	missense	Exon 19 of 64	NP_774959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.2392C>A	p.His798Asn	missense	Exon 19 of 65	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.2392C>A	p.His798Asn	missense	Exon 19 of 65	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.2392C>A	p.His798Asn	missense	Exon 19 of 64	ENSP00000345694.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Familial temporal lobe epilepsy 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.76
MutPred		0.46		Gain of sheet (P = 0.0827)
MVP		0.51
MPC		0.34
ClinPred		0.92	D
GERP RS		6.1
Varity_R		0.51
gMVP		0.86
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs794727996; hg19: chr7-103275945;