chr7-103495791-CCTT-C

Variant names:

• chr7-103495791-CCTT-C
• rs762015967
• NM_005045.4:c.9298_9300delAAG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS1

The NM_005045.4(RELN):​c.9298_9300delAAG​(p.Lys3100del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000122 in 1,613,922 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: RELN NM_005045.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 5.93
• Publications: 0 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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005045.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 7-103495791-CCTT-C is Benign according to our data. Variant chr7-103495791-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198005.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000565 (86/152098) while in subpopulation AFR AF = 0.00205 (85/41490). AF 95% confidence interval is 0.0017. There are 1 homozygotes in GnomAd4. There are 35 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.9298_9300delAAG	p.Lys3100del	conservative_inframe_deletion	Exon 57 of 65	NP_005036.2
	RELN	NM_173054.3		c.9298_9300delAAG	p.Lys3100del	conservative_inframe_deletion	Exon 57 of 64	NP_774959.1	P78509-2
	SLC26A5-AS1	NR_110141.1		n.1366-8609_1366-8607delCTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.9298_9300delAAG	p.Lys3100del	conservative_inframe_deletion	Exon 57 of 65	ENSP00000392423.1	P78509-1
	SLC26A5-AS1	ENST00000422488.1	TSL:1	n.1366-8609_1366-8607delCTT		intron	N/A
	RELN	ENST00000424685.3	TSL:5	c.9298_9300delAAG	p.Lys3100del	conservative_inframe_deletion	Exon 57 of 65	ENSP00000388446.3	J3KQ66

Frequencies

GnomAD3 genomes AF: 0.000566 AC: 86 AN: 151980 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251338 AF XY: 0.000125

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000759 AC: 111 AN: 1461824 Hom.: 0 AF XY: 0.0000660 AC XY: 48 AN XY: 727218

African (AFR) AF: 0.00278 AC: 93 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111974

Other (OTH) AF: 0.0000994 AC: 6 AN: 60392

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152098 Hom.: 1 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74342

African (AFR) AF: 0.00205 AC: 85 AN: 41490

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (2)
-	1	-	Familial temporal lobe epilepsy 7 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=58/42	polymorphism

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: rs762015967; hg19: chr7-103136238;