7-103630182-GAA-GAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_005045.4(RELN):c.2466-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0622 in 1,051,372 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.072 ( 0 hom. )

Consequence

RELN
NM_005045.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.884

Publications

1 publications found

Variant links:

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, Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

RELN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005045.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 7-103630182-G-GA is Benign according to our data. Variant chr7-103630182-G-GA is described in ClinVar as Benign. ClinVar VariationId is 195496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000354 (49/138536) while in subpopulation AFR AF = 0.000344 (13/37754). AF 95% confidence interval is 0.000203. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2466-7dupT		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.2466-7dupT		splice_region intron	N/A	NP_774959.1	P78509-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RELN	ENST00000428762.6	TSL:5 MANE Select	c.2466-7_2466-6insT	splice_region intron	N/A	ENSP00000392423.1	P78509-1
RELN	ENST00000424685.3	TSL:5	c.2466-7_2466-6insT	splice_region intron	N/A	ENSP00000388446.3	J3KQ66
RELN	ENST00000343529.9	TSL:5	c.2466-7_2466-6insT	splice_region intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes

AF:

0.000332

AC:

AN:

138474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000209

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000284

Gnomad OTH

AF:

0.000538

GnomAD2 exomes

AF:

0.0455

AC:

4612

AN:

101368

AF XY:

0.0444

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.0619

Gnomad ASJ exome

AF:

0.0692

Gnomad EAS exome

AF:

0.0408

Gnomad FIN exome

AF:

0.0628

Gnomad NFE exome

AF:

0.0353

Gnomad OTH exome

AF:

0.0573

GnomAD4 exome

AF:

0.0716

AC:

65364

AN:

912836

Hom.:

Cov.:

AF XY:

0.0697

AC XY:

31188

AN XY:

447198

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0753

AC:

1490

AN:

19784

American (AMR)

AF:

0.0517

AC:

1163

AN:

22500

Ashkenazi Jewish (ASJ)

AF:

0.0726

AC:

970

AN:

13358

East Asian (EAS)

AF:

0.0573

AC:

1166

AN:

20354

South Asian (SAS)

AF:

0.0488

AC:

2172

AN:

44490

European-Finnish (FIN)

AF:

0.0534

AC:

1571

AN:

29408

Middle Eastern (MID)

AF:

0.0485

AC:

186

AN:

3836

European-Non Finnish (NFE)

AF:

0.0746

AC:

53976

AN:

723348

Other (OTH)

AF:

0.0747

AC:

2670

AN:

35758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

8169

16338

24507

32676

40845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

2412

4824

7236

9648

12060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000354

AC:

AN:

138536

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

AN XY:

67028

show subpopulations

African (AFR)

AF:

0.000344

AC:

AN:

37754

American (AMR)

AF:

0.000288

AC:

AN:

13896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3294

East Asian (EAS)

AF:

0.000210

AC:

AN:

4766

South Asian (SAS)

AF:

0.000226

AC:

AN:

4420

European-Finnish (FIN)

AF:

0.00138

AC:

AN:

7944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.000284

AC:

AN:

63454

Other (OTH)

AF:

0.000532

AC:

AN:

1880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0634

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over