2-108946039-C-T

Variant names:

• chr2-108946039-C-T
• rs260714
• NM_022336.4:c.-18-15007G>A

Variant summary

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

The NM_022336.4(EDAR):​c.-18-15007G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,172 control chromosomes in the GnomAD database, including 15,187 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 0.35 (15187 hom., cov: 33)
• Consequence: EDAR NM_022336.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 10 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022336.4. 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
	EDAR	NM_022336.4	MANE Select	c.-18-15007G>A		intron	N/A	NP_071731.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	ENST00000258443.7	TSL:1 MANE Select	c.-18-15007G>A		intron	N/A	ENSP00000258443.2
	EDAR	ENST00000376651.1	TSL:2	c.-18-15007G>A		intron	N/A	ENSP00000365839.1
	EDAR	ENST00000409271.5	TSL:2	c.-134-5713G>A		intron	N/A	ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53114 AN: 152054 Hom.: 15130 Cov.: 33

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.952

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.350 AC: 53237 AN: 152172 Hom.: 15187 Cov.: 33 AF XY: 0.353 AC XY: 26272 AN XY: 74398

African (AFR) AF: 0.698 AC: 28963 AN: 41486

American (AMR) AF: 0.438 AC: 6701 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3472

East Asian (EAS) AF: 0.952 AC: 4935 AN: 5184

South Asian (SAS) AF: 0.202 AC: 971 AN: 4818

European-Finnish (FIN) AF: 0.184 AC: 1946 AN: 10598

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8511 AN: 68008

Other (OTH) AF: 0.318 AC: 672 AN: 2112

Alfa AF: 0.191 Hom.: 15582

Bravo AF: 0.394

Asia WGS AF: 0.601 AC: 2086 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.53
DANN	Benign	0.20
PhyloP100		-1.0
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: rs260714; hg19: chr2-109562495;