rs12623957

chr2-108897198-G-Achr2-108897198-G-Cchr2-108897198-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022336.4(EDAR):c.1056C>T(p.Cys352=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 1.71

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 155865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108897198-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
EDAR	NM_022336.4	c.1056C>T	p.Cys352=	synonymous_variant	12/12	ENST00000258443.7
EDAR	XM_006712204.2	c.1152C>T	p.Cys384=	synonymous_variant	11/11
RANBP2	XM_047445367.1	c.8370+124152G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.1056C>T	p.Cys352=	synonymous_variant	12/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.1152C>T	p.Cys384=	synonymous_variant	11/11	2
EDAR	ENST00000409271.5	c.1152C>T	p.Cys384=	synonymous_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111136 AN: 151894 Hom.: 43284 Cov.: 32

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

GnomAD3 exomes AF: 0.821 AC: 202321 AN: 246310 Hom.: 84939 AF XY: 0.822 AC XY: 109812 AN XY: 133538

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 SAS exome AF: 0.757

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.: 64 AF XY: 0.819 AC XY: 595477 AN XY: 726978

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.885

Gnomad4 ASJ exome AF: 0.884

Gnomad4 EAS exome AF: 0.904

Gnomad4 SAS exome AF: 0.752

Gnomad4 FIN exome AF: 0.878

Gnomad4 NFE exome AF: 0.829

Gnomad4 OTH exome AF: 0.817

GnomAD4 genome AF: 0.731 AC: 111174 AN: 152012 Hom.: 43294 Cov.: 32 AF XY: 0.737 AC XY: 54791 AN XY: 74326

Gnomad4 AFR AF: 0.439

Gnomad4 AMR AF: 0.833

Gnomad4 ASJ AF: 0.882

Gnomad4 EAS AF: 0.950

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.892

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.780

Alfa AF: 0.807 Hom.: 64066

Bravo AF: 0.718

Asia WGS AF: 0.789 AC: 2743 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hypohidrotic Ectodermal Dysplasia, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Hypohidrotic ectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.4
Dann	Benign	0.56

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

Other links and lift over

dbSNP: rs12623957; hg19: chr2-109513654; COSMIC: COSV51508095;