7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr7-103989356-T-TGCCGCCGCCGCCGCCGCCGCCGCC
• rs55656324
• NM_005045.4:c.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_005045.4(RELN):​c.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC 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 0.00080 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000096 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000795 (118/148368) while in subpopulation EAS AF = 0.00681 (32/4698). AF 95% confidence interval is 0.00496. There are 0 homozygotes in GnomAd4. There are 56 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

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.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC		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.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-24_-1dupGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.000796 AC: 118 AN: 148270 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00679

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000960 AC: 121 AN: 1259834 Hom.: 3 Cov.: 36 AF XY: 0.0000935 AC XY: 58 AN XY: 620568

African (AFR) AF: 0.000851 AC: 21 AN: 24664

American (AMR) AF: 0.00 AC: 0 AN: 21234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21048

East Asian (EAS) AF: 0.000480 AC: 13 AN: 27096

South Asian (SAS) AF: 0.000213 AC: 12 AN: 56308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37800

Middle Eastern (MID) AF: 0.000240 AC: 1 AN: 4160

European-Non Finnish (NFE) AF: 0.0000571 AC: 58 AN: 1015452

Other (OTH) AF: 0.000307 AC: 16 AN: 52072

GnomAD4 genome AF: 0.000795 AC: 118 AN: 148368 Hom.: 0 Cov.: 0 AF XY: 0.000774 AC XY: 56 AN XY: 72354

African (AFR) AF: 0.00171 AC: 69 AN: 40318

American (AMR) AF: 0.000332 AC: 5 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00681 AC: 32 AN: 4698

South Asian (SAS) AF: 0.00107 AC: 5 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10062

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

European-Non Finnish (NFE) AF: 0.000105 AC: 7 AN: 66874

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 609

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lissencephaly, Recessive (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;