2-108906291-CTT-CT

Variant names:

• chr2-108906291-CT-C
• rs3833574
• NM_022336.4:c.1024+16delA

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 155863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022336.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	NM_022336.4	MANE Select	c.1024+16delA		intron	N/A	NP_071731.1	Q9UNE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	ENST00000258443.7	TSL:1 MANE Select	c.1024+16delA		intron	N/A	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.1120+16delA		intron	N/A	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.1120+16delA		intron	N/A	ENSP00000386371.1	Q9UNE0-2

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

GnomAD2 exomes AF: 0.109 AC: 27304 AN: 251332 AF XY: 0.108

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 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

African (AFR) AF: 0.515 AC: 17230 AN: 33446

American (AMR) AF: 0.0662 AC: 2960 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 1499 AN: 26096

East Asian (EAS) AF: 0.119 AC: 4704 AN: 39662

South Asian (SAS) AF: 0.221 AC: 19032 AN: 86198

European-Finnish (FIN) AF: 0.0230 AC: 1229 AN: 53334

Middle Eastern (MID) AF: 0.143 AC: 819 AN: 5746

European-Non Finnish (NFE) AF: 0.0679 AC: 75335 AN: 1108720

Other (OTH) AF: 0.109 AC: 6596 AN: 60250

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

African (AFR) AF: 0.495 AC: 20551 AN: 41478

American (AMR) AF: 0.108 AC: 1653 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 190 AN: 3472

East Asian (EAS) AF: 0.0826 AC: 426 AN: 5160

South Asian (SAS) AF: 0.232 AC: 1118 AN: 4810

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10618

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.0660 AC: 4487 AN: 67984

Other (OTH) AF: 0.154 AC: 324 AN: 2106

Alfa AF: 0.0454 Hom.: 66

Bravo AF: 0.206

Asia WGS AF: 0.245 AC: 852 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3833574; hg19: chr2-109522747; COSMIC: COSV51503681;