rs260690

Variant names:

• chr2-108963282-C-A
• rs260690
• NM_022336.4:c.-19+25678G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022336.4(EDAR):​c.-19+25678G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 152,108 control chromosomes in the GnomAD database, including 45,438 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (45438 hom., cov: 33)
• Consequence: EDAR NM_022336.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 22 publications found

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4	c.-19+25678G>T		intron_variant	Intron 1 of 11	ENST00000258443.7	NP_071731.1
RANBP2	XM_047445367.1	c.8370+190236C>A		intron_variant	Intron 24 of 24		XP_047301323.1
EDAR	XM_006712204.2	c.-19+25678G>T		intron_variant	Intron 1 of 10		XP_006712267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.-19+25678G>T		intron_variant	Intron 1 of 11	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.-19+25678G>T		intron_variant	Intron 1 of 10	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.-134-22956G>T		intron_variant	Intron 1 of 11	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111078 AN: 151988 Hom.: 45436 Cov.: 33

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.990

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.0614

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.764

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.730 AC: 111102 AN: 152108 Hom.: 45438 Cov.: 33 AF XY: 0.725 AC XY: 53881 AN XY: 74356

African (AFR) AF: 0.445 AC: 18431 AN: 41460

American (AMR) AF: 0.623 AC: 9529 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3147 AN: 3472

East Asian (EAS) AF: 0.0617 AC: 319 AN: 5172

South Asian (SAS) AF: 0.887 AC: 4278 AN: 4824

European-Finnish (FIN) AF: 0.851 AC: 9008 AN: 10590

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63638 AN: 67988

Other (OTH) AF: 0.756 AC: 1593 AN: 2108

Alfa AF: 0.860 Hom.: 240147

Bravo AF: 0.688

Asia WGS AF: 0.456 AC: 1590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.032
DANN	Benign	0.52
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs260690; hg19: chr2-109579738;