rs260632

Variant names:

• chr2-108910513-G-A
• rs260632
• NM_022336.4:c.750C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-108910513-G-A
• chr2-108910513-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022336.4(EDAR):​c.750C>T​(p.Ser250Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,613,114 control chromosomes in the GnomAD database, including 664,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (62349 hom., cov: 29)
  • Exomes 𝑓: 0.91 (601889 hom.)
• Consequence: EDAR NM_022336.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -1.83
• Publications: 25 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, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-108910513-G-A is Benign according to our data. Variant chr2-108910513-G-A is described in ClinVar as Benign. ClinVar VariationId is 155870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.750C>T	p.Ser250Ser	synonymous	Exon 9 of 12	NP_071731.1	Q9UNE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	ENST00000258443.7	TSL:1 MANE Select	c.750C>T	p.Ser250Ser	synonymous	Exon 9 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.846C>T	p.Ser282Ser	synonymous	Exon 8 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.846C>T	p.Ser282Ser	synonymous	Exon 9 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.905 AC: 137465 AN: 151850 Hom.: 62301 Cov.: 29

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.920

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.917

GnomAD2 exomes AF: 0.919 AC: 230602 AN: 250932 AF XY: 0.919

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.952

Gnomad ASJ exome AF: 0.944

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.900

Gnomad NFE exome AF: 0.903

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.907 AC: 1325848 AN: 1461146 Hom.: 601889 Cov.: 46 AF XY: 0.907 AC XY: 659485 AN XY: 726894

African (AFR) AF: 0.885 AC: 29600 AN: 33454

American (AMR) AF: 0.950 AC: 42462 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 24569 AN: 26106

East Asian (EAS) AF: 0.999 AC: 39654 AN: 39694

South Asian (SAS) AF: 0.920 AC: 79349 AN: 86204

European-Finnish (FIN) AF: 0.901 AC: 48141 AN: 53416

Middle Eastern (MID) AF: 0.926 AC: 5339 AN: 5768

European-Non Finnish (NFE) AF: 0.901 AC: 1001549 AN: 1111432

Other (OTH) AF: 0.914 AC: 55185 AN: 60374

GnomAD4 genome AF: 0.905 AC: 137573 AN: 151968 Hom.: 62349 Cov.: 29 AF XY: 0.907 AC XY: 67368 AN XY: 74284

African (AFR) AF: 0.882 AC: 36541 AN: 41424

American (AMR) AF: 0.934 AC: 14266 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3251 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5113 AN: 5130

South Asian (SAS) AF: 0.920 AC: 4421 AN: 4804

European-Finnish (FIN) AF: 0.911 AC: 9650 AN: 10592

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.904 AC: 61420 AN: 67960

Other (OTH) AF: 0.917 AC: 1932 AN: 2106

Alfa AF: 0.905 Hom.: 44065

Bravo AF: 0.906

Asia WGS AF: 0.939 AC: 3264 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (1)
-	-	1	Hypohidrotic ectodermal dysplasia (1)
-	-	1	Hypohidrotic Ectodermal Dysplasia, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.34
DANN	Benign	0.42
PhyloP100		-1.8
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: rs260632; hg19: chr2-109526969; COSMIC: COSV51501206;