rs260632

Positions:

• chr2-108910513-G-A
• chr2-108910513-G-C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -1.83

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: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]

ACMG classification

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/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.750C>T	p.Ser250Ser	synonymous_variant	9/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.846C>T	p.Ser282Ser	synonymous_variant	8/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+137467G>A		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.750C>T	p.Ser250Ser	synonymous_variant	9/12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.846C>T	p.Ser282Ser	synonymous_variant	8/11	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.846C>T	p.Ser282Ser	synonymous_variant	9/12	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.905 AC: 137465 AN: 151850 Hom.: 62301 Cov.: 29

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

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.: 46 AF XY: 0.907 AC XY: 659485 AN XY: 726894

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.: 29 AF XY: 0.907 AC XY: 67368 AN XY: 74284

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:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Hypohidrotic Ectodermal Dysplasia, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

Other links and lift over

dbSNP: rs260632; hg19: chr2-109526969; COSMIC: COSV51501206;