2-108910513-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: -1.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 155870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108910513-G-A is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4 link	c.750C>T	p.Ser250Ser	synonymous_variant	Exon 9 of 12	ENST00000258443.7	NP_071731.1	Q9UNE0-1
EDAR	XM_006712204.2 link	c.846C>T	p.Ser282Ser	synonymous_variant	Exon 8 of 11		XP_006712267.1	Q9UNE0-2
RANBP2	XM_047445367.1 link	c.8370+137467G>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.750C>T	p.Ser250Ser	synonymous_variant	Exon 9 of 12	1	NM_022336.4	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1 link	c.846C>T	p.Ser282Ser	synonymous_variant	Exon 8 of 11	2		ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5 link	c.846C>T	p.Ser282Ser	synonymous_variant	Exon 9 of 12	2		ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.905

AC:

137465

AN:

151850

Hom.:

62301

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.919

AC:

230602

AN:

250932

Hom.:

106190

AF XY:

0.919

AC XY:

124564

AN XY:

135614

show subpopulations

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 SAS exome

AF:

0.921

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.:

AF XY:

0.907

AC XY:

659485

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.885

Gnomad4 AMR exome

AF:

0.950

Gnomad4 ASJ exome

AF:

0.941

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.920

Gnomad4 FIN exome

AF:

0.901

Gnomad4 NFE exome

AF:

0.901

Gnomad4 OTH exome

AF:

0.914

GnomAD4 genome

AF:

0.905

AC:

137573

AN:

151968

Hom.:

62349

Cov.:

AF XY:

0.907

AC XY:

67368

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.882

Gnomad4 AMR

AF:

0.934

Gnomad4 ASJ

AF:

0.937

Gnomad4 EAS

AF:

0.997

Gnomad4 SAS

AF:

0.920

Gnomad4 FIN

AF:

0.911

Gnomad4 NFE

AF:

0.904

Gnomad4 OTH

AF:

0.917

Alfa

AF:

0.904

Hom.:

34079

Bravo

AF:

0.906

Asia WGS

AF:

0.939

AC:

3264

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not expected to have clinical significance because it has been s een in 90% (7759/8600) of European American chromosomes and 88.5% (3898/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs260632). -

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

-0.81

CADD

Benign

0.34

DANN

Benign

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over