7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr7-103989356-T-TGCCGCCGCCGCCGCCGCCGCC
• rs55656324
• NM_005045.4:c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005045.4(RELN):​c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (32 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00407 (604/148366) while in subpopulation EAS AF = 0.0292 (137/4696). AF 95% confidence interval is 0.0252. There are 6 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 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.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		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.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 601 AN: 148268 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.000871

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.00490

Gnomad FIN AF: 0.000596

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.00196

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00118 AC: 1487 AN: 1259304 Hom.: 32 Cov.: 36 AF XY: 0.00111 AC XY: 688 AN XY: 620268

African (AFR) AF: 0.000892 AC: 22 AN: 24656

American (AMR) AF: 0.000377 AC: 8 AN: 21222

Ashkenazi Jewish (ASJ) AF: 0.000285 AC: 6 AN: 21048

East Asian (EAS) AF: 0.00323 AC: 87 AN: 26924

South Asian (SAS) AF: 0.000764 AC: 43 AN: 56304

European-Finnish (FIN) AF: 0.000132 AC: 5 AN: 37796

Middle Eastern (MID) AF: 0.000721 AC: 3 AN: 4160

European-Non Finnish (NFE) AF: 0.00123 AC: 1244 AN: 1015148

Other (OTH) AF: 0.00133 AC: 69 AN: 52046

GnomAD4 genome AF: 0.00407 AC: 604 AN: 148366 Hom.: 6 Cov.: 0 AF XY: 0.00408 AC XY: 295 AN XY: 72352

African (AFR) AF: 0.00325 AC: 131 AN: 40318

American (AMR) AF: 0.00153 AC: 23 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.000871 AC: 3 AN: 3446

East Asian (EAS) AF: 0.0292 AC: 137 AN: 4696

South Asian (SAS) AF: 0.00490 AC: 23 AN: 4692

European-Finnish (FIN) AF: 0.000596 AC: 6 AN: 10062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00414 AC: 277 AN: 66874

Other (OTH) AF: 0.00194 AC: 4 AN: 2060

Alfa AF: 0.00170 Hom.: 609

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Lissencephaly, Recessive (1)
-	1	-	not specified (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; COSMIC: COSV100632508;