rs12623957

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022336.4(EDAR):c.1056C>T(p.Cys352Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 1,613,426 control chromosomes in the GnomAD database, including 539,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 43294 hom., cov: 32)

Exomes 𝑓: 0.82 ( 495792 hom. )

Consequence

EDAR
NM_022336.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: 1.71

Publications

23 publications found

Variant links:

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]

EDAR links:

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

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 2-108897198-G-A is Benign according to our data. Variant chr2-108897198-G-A is described in ClinVar as Benign. ClinVar VariationId is 155865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.71 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4 link	c.1056C>T	p.Cys352Cys	synonymous_variant	Exon 12 of 12	ENST00000258443.7	NP_071731.1	Q9UNE0-1
EDAR	XM_006712204.2 link	c.1152C>T	p.Cys384Cys	synonymous_variant	Exon 11 of 11		XP_006712267.1	Q9UNE0-2
RANBP2	XM_047445367.1 link	c.8370+124152G>A		intron_variant	Intron 24 of 24		XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDAR	ENST00000258443.7 link	c.1056C>T	p.Cys352Cys	synonymous_variant	Exon 12 of 12	1	NM_022336.4	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1 link	c.1152C>T	p.Cys384Cys	synonymous_variant	Exon 11 of 11	2		ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5 link	c.1152C>T	p.Cys384Cys	synonymous_variant	Exon 12 of 12	2		ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

111136

AN:

151894

Hom.:

43284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.439

Gnomad AMI

AF:

0.775

Gnomad AMR

AF:

0.833

Gnomad ASJ

AF:

0.882

Gnomad EAS

AF:

0.950

Gnomad SAS

AF:

0.750

Gnomad FIN

AF:

0.892

Gnomad MID

AF:

0.785

Gnomad NFE

AF:

0.834

Gnomad OTH

AF:

0.778

GnomAD2 exomes

AF:

0.821

AC:

202321

AN:

246310

AF XY:

0.822

show subpopulations

Gnomad AFR exome

AF:

0.428

Gnomad AMR exome

AF:

0.894

Gnomad ASJ exome

AF:

0.888

Gnomad EAS exome

AF:

0.964

Gnomad FIN exome

AF:

0.880

Gnomad NFE exome

AF:

0.832

Gnomad OTH exome

AF:

0.832

GnomAD4 exome

AF:

0.821

AC:

1199428

AN:

1461414

Hom.:

495792

Cov.:

AF XY:

0.819

AC XY:

595477

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.428

AC:

14329

AN:

33476

American (AMR)

AF:

0.885

AC:

39598

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.884

AC:

23091

AN:

26134

East Asian (EAS)

AF:

0.904

AC:

35896

AN:

39698

South Asian (SAS)

AF:

0.752

AC:

64818

AN:

86248

European-Finnish (FIN)

AF:

0.878

AC:

46567

AN:

53024

Middle Eastern (MID)

AF:

0.778

AC:

4486

AN:

5768

European-Non Finnish (NFE)

AF:

0.829

AC:

921320

AN:

1111954

Other (OTH)

AF:

0.817

AC:

49323

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

12192

24384

36576

48768

60960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20954

41908

62862

83816

104770

<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:

0.731

AC:

111174

AN:

152012

Hom.:

43294

Cov.:

AF XY:

0.737

AC XY:

54791

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.439

AC:

18160

AN:

41404

American (AMR)

AF:

0.833

AC:

12738

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.882

AC:

3064

AN:

3472

East Asian (EAS)

AF:

0.950

AC:

4902

AN:

5160

South Asian (SAS)

AF:

0.751

AC:

3603

AN:

4800

European-Finnish (FIN)

AF:

0.892

AC:

9449

AN:

10588

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.834

AC:

56683

AN:

67992

Other (OTH)

AF:

0.780

AC:

1643

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1246

2491

3737

4982

6228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.790

Hom.:

84910

Bravo

AF:

0.718

Asia WGS

AF:

0.789

AC:

2743

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Nov 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypohidrotic Ectodermal Dysplasia, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.4

(source)

DANN

Benign

0.56

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over