2-108923457-C-T

Position:

chr2-108923457-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022336.4(EDAR):c.357-4G>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003956

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.633

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:):

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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	MANE
EDAR	NM_022336.4 linkuse as main transcript	c.357-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000258443.7
EDAR	XM_006712204.2 linkuse as main transcript	c.357-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RANBP2	XM_047445367.1 linkuse as main transcript	c.8370+150411C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7 linkuse as main transcript	c.357-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_022336.4	P1	Q9UNE0-1
EDAR	ENST00000376651.1 linkuse as main transcript	c.357-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2			Q9UNE0-2
EDAR	ENST00000409271.5 linkuse as main transcript	c.357-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2			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

GnomAD3 exomes

AF:

0.0579

AC:

14547

AN:

251412

Hom.:

626

AF XY:

0.0604

AC XY:

8211

AN XY:

135868

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 SAS exome

AF:

0.114

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

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.0364

Gnomad4 ASJ exome

AF:

0.0712

Gnomad4 EAS exome

AF:

0.0631

Gnomad4 SAS exome

AF:

0.117

Gnomad4 FIN exome

AF:

0.0201

Gnomad4 NFE exome

AF:

0.0540

Gnomad4 OTH exome

AF:

0.0633

GnomAD4 genome

AF:

0.0741

AC:

11275

AN:

152154

Hom.:

580

Cov.:

AF XY:

0.0726

AC XY:

5401

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.0574

Gnomad4 ASJ

AF:

0.0651

Gnomad4 EAS

AF:

0.0295

Gnomad4 SAS

AF:

0.112

Gnomad4 FIN

AF:

0.0157

Gnomad4 NFE

AF:

0.0520

Gnomad4 OTH

AF:

0.0653

Alfa

AF:

0.0624

Hom.:

202

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2014	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) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypohidrotic Ectodermal Dysplasia, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypohidrotic ectodermal dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.8

DANN

Benign

0.66

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

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