2-108923457-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022336.4(EDAR):c.357-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,166 control chromosomes in the GnomAD database, including 3,762 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 580 hom., cov: 33)

Exomes 𝑓: 0.059 ( 3182 hom. )

Consequence

EDAR
NM_022336.4 splice_region, intron

Scores

Splicing: ADA: 0.00003956

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.633

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-108923457-C-T is Benign according to our data. Variant chr2-108923457-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
EDAR	NM_022336.4 link	c.357-4G>A	splice_region_variant, intron_variant	Intron 4 of 11	ENST00000258443.7	NP_071731.1	Q9UNE0-1
RANBP2	XM_047445367.1 link	c.8370+150411C>T	intron_variant	Intron 24 of 24		XP_047301323.1
EDAR	XM_006712204.2 link	c.357-4G>A	splice_region_variant, intron_variant	Intron 4 of 10		XP_006712267.1	Q9UNE0-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EDAR	ENST00000258443.7 link	c.357-4G>A	splice_region_variant, intron_variant	Intron 4 of 11	1	NM_022336.4	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1 link	c.357-4G>A	splice_region_variant, intron_variant	Intron 4 of 10	2		ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5 link	c.357-4G>A	splice_region_variant, intron_variant	Intron 5 of 11	2		ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.0740

AC:

11249

AN:

152034

Hom.:

577

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0575

Gnomad ASJ

AF:

0.0651

Gnomad EAS

AF:

0.0295

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0520

Gnomad OTH

AF:

0.0660

GnomAD2 exomes

AF:

0.0579

AC:

14547

AN:

251412

AF XY:

0.0604

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.0333

Gnomad ASJ exome

AF:

0.0724

Gnomad EAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0530

Gnomad OTH exome

AF:

0.0561

GnomAD4 exome

AF:

0.0591

AC:

86408

AN:

1461012

Hom.:

3182

Cov.:

AF XY:

0.0610

AC XY:

44327

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.143

AC:

4787

AN:

33450

American (AMR)

AF:

0.0364

AC:

1629

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0712

AC:

1861

AN:

26130

East Asian (EAS)

AF:

0.0631

AC:

2504

AN:

39690

South Asian (SAS)

AF:

0.117

AC:

10095

AN:

86214

European-Finnish (FIN)

AF:

0.0201

AC:

1073

AN:

53408

Middle Eastern (MID)

AF:

0.105

AC:

604

AN:

5762

European-Non Finnish (NFE)

AF:

0.0540

AC:

60033

AN:

1111276

Other (OTH)

AF:

0.0633

AC:

3822

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

4116

8232

12348

16464

20580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2354

4708

7062

9416

11770

<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:

0.0741

AC:

11275

AN:

152154

Hom.:

580

Cov.:

AF XY:

0.0726

AC XY:

5401

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.135

AC:

5608

AN:

41472

American (AMR)

AF:

0.0574

AC:

877

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0651

AC:

226

AN:

3470

East Asian (EAS)

AF:

0.0295

AC:

153

AN:

5182

South Asian (SAS)

AF:

0.112

AC:

541

AN:

4822

European-Finnish (FIN)

AF:

0.0157

AC:

167

AN:

10606

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0520

AC:

3534

AN:

68002

Other (OTH)

AF:

0.0653

AC:

138

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

504

1009

1513

2018

2522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0626

Hom.:

262

Bravo

AF:

0.0767

Asia WGS

AF:

0.0880

AC:

307

AN:

3478

EpiCase

AF:

0.0597

EpiControl

AF:

0.0607

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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 5.4% (469/8600) of European American chromosomes and 13.7% (606/4460) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs748225) -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Jan 13, 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

Jan 30, 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

-0.80

CADD

Benign

1.8

(source)

DANN

Benign

0.66

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.0020

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