2-108910783-C-T

Position:

• chr2-108910783-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022336.4(EDAR):​c.723G>A​(p.Glu241Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,166 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (78 hom.)
• Consequence: EDAR NM_022336.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.341

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-108910783-C-T is Benign according to our data. Variant chr2-108910783-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 463881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.341 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00476 (724/152108) while in subpopulation SAS AF= 0.0225 (108/4806). AF 95% confidence interval is 0.019. There are 6 homozygotes in gnomad4. There are 376 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.723G>A	p.Glu241Glu	synonymous_variant	8/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.819G>A	p.Glu273Glu	synonymous_variant	7/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+137737C>T		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.723G>A	p.Glu241Glu	synonymous_variant	8/12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.819G>A	p.Glu273Glu	synonymous_variant	7/11	2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.819G>A	p.Glu273Glu	synonymous_variant	8/12	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 723 AN: 151990 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00754 AC: 1894 AN: 251210 Hom.: 21 AF XY: 0.00794 AC XY: 1078 AN XY: 135778

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0238

Gnomad SAS exome AF: 0.0197

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00703 AC: 10268 AN: 1461058 Hom.: 78 Cov.: 34 AF XY: 0.00737 AC XY: 5356 AN XY: 726802

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0321

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.000675

Gnomad4 NFE exome AF: 0.00594

Gnomad4 OTH exome AF: 0.00620

GnomAD4 genome AF: 0.00476 AC: 724 AN: 152108 Hom.: 6 Cov.: 32 AF XY: 0.00506 AC XY: 376 AN XY: 74342

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00465

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.0225

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00485 Hom.: 3

Bravo AF: 0.00464

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

HAIR MORPHOLOGY 1;C3887494:Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

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. -

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

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.0
DANN	Benign	0.63

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: rs3749108; hg19: chr2-109527239;