2-108906291-CTT-CT

Position:

• chr2-108906291-CTT-CT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_022336.4(EDAR):​c.1024+16delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 1,610,286 control chromosomes in the GnomAD database, including 16,164 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5669 hom., cov: 30)
  • Exomes 𝑓: 0.089 (10495 hom.)
• Consequence: EDAR NM_022336.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.278

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 -16 ACMG points.

• BP6: Variant 2-108906291-CT-C is Benign according to our data. Variant chr2-108906291-CT-C is described in ClinVar as [Benign]. Clinvar id is 155863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108906291-CT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.1024+16delA		intron_variant		ENST00000258443.7	NP_071731.1
RANBP2	XM_047445367.1	c.8370+133253delT		intron_variant			XP_047301323.1
EDAR	XM_006712204.2	c.1120+16delA		intron_variant			XP_006712267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.1024+16delA		intron_variant		1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651.1	c.1120+16delA		intron_variant		2		ENSP00000365839.1
EDAR	ENST00000409271.5	c.1120+16delA		intron_variant		2		ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28923 AN: 152010 Hom.: 5621 Cov.: 30

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0547

Gnomad EAS AF: 0.0828

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.109 AC: 27304 AN: 251332 Hom.: 3367 AF XY: 0.108 AC XY: 14724 AN XY: 135832

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.0606

Gnomad ASJ exome AF: 0.0559

Gnomad EAS exome AF: 0.0653

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0666

Gnomad OTH exome AF: 0.0887

GnomAD4 exome AF: 0.0887 AC: 129404 AN: 1458158 Hom.: 10495 Cov.: 32 AF XY: 0.0916 AC XY: 66479 AN XY: 725616

Gnomad4 AFR exome AF: 0.515

Gnomad4 AMR exome AF: 0.0662

Gnomad4 ASJ exome AF: 0.0574

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.0679

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.191 AC: 29034 AN: 152128 Hom.: 5669 Cov.: 30 AF XY: 0.187 AC XY: 13940 AN XY: 74372

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0547

Gnomad4 EAS AF: 0.0826

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0660

Gnomad4 OTH AF: 0.154

Alfa AF: 0.0454 Hom.: 66

Bravo AF: 0.206

Asia WGS AF: 0.245 AC: 852 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs3833574; hg19: chr2-109522747;