7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr7-103989356-T-TGCCGCCGCCGCC
• rs55656324
• NM_005045.4:c.-12_-1dupGGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005045.4(RELN):​c.-12_-1dupGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (71 hom., cov: 0)
  • Exomes 𝑓: 0.011 (239 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.06
• Publications: 2 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 -9 ACMG points.

• BP6: Variant 7-103989356-T-TGCCGCCGCCGCC is Benign according to our data. Variant chr7-103989356-T-TGCCGCCGCCGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358424.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 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.-12_-1dupGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR	Exon 1 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.-12_-1dupGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3573 AN: 148246 Hom.: 71 Cov.: 0

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.0617

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00754

Gnomad EAS AF: 0.00382

Gnomad SAS AF: 0.0287

Gnomad FIN AF: 0.00567

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0319

GnomAD2 exomes AF: 0.00146 AC: 93 AN: 63892 AF XY: 0.00178

Gnomad AFR exome AF: 0.000613

Gnomad AMR exome AF: 0.000664

Gnomad ASJ exome AF: 0.000999

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000597

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0110 AC: 13805 AN: 1258134 Hom.: 239 Cov.: 36 AF XY: 0.0109 AC XY: 6725 AN XY: 619642

African (AFR) AF: 0.0509 AC: 1252 AN: 24600

American (AMR) AF: 0.00481 AC: 102 AN: 21202

Ashkenazi Jewish (ASJ) AF: 0.00447 AC: 94 AN: 21032

East Asian (EAS) AF: 0.00459 AC: 124 AN: 27002

South Asian (SAS) AF: 0.0126 AC: 707 AN: 55966

European-Finnish (FIN) AF: 0.00405 AC: 153 AN: 37758

Middle Eastern (MID) AF: 0.0238 AC: 99 AN: 4154

European-Non Finnish (NFE) AF: 0.0104 AC: 10562 AN: 1014442

Other (OTH) AF: 0.0137 AC: 712 AN: 51978

GnomAD4 genome AF: 0.0241 AC: 3578 AN: 148344 Hom.: 71 Cov.: 0 AF XY: 0.0243 AC XY: 1758 AN XY: 72342

African (AFR) AF: 0.0542 AC: 2184 AN: 40310

American (AMR) AF: 0.0171 AC: 258 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00754 AC: 26 AN: 3446

East Asian (EAS) AF: 0.00383 AC: 18 AN: 4696

South Asian (SAS) AF: 0.0288 AC: 135 AN: 4692

European-Finnish (FIN) AF: 0.00567 AC: 57 AN: 10058

Middle Eastern (MID) AF: 0.0108 AC: 3 AN: 278

European-Non Finnish (NFE) AF: 0.0116 AC: 777 AN: 66866

Other (OTH) AF: 0.0316 AC: 65 AN: 2060

Alfa AF: 0.00263 Hom.: 609

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	-	Lissencephaly, Recessive (1)
-	-	1	not provided (1)
-	-	1	RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55656324; hg19: chr7-103629803;