chr2-108894481-G-A

Variant names:

• chr2-108894481-G-A
• rs1478517
• NM_022336.4:c.*2426C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022336.4(EDAR):​c.*2426C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 151,646 control chromosomes in the GnomAD database, including 26,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (26136 hom., cov: 31)
  • Exomes 𝑓: 0.64 (91 hom.)
• Consequence: EDAR NM_022336.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0670
• Publications: 6 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, ClinGen, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-108894481-G-A is Benign according to our data. Variant chr2-108894481-G-A is described in ClinVar as Benign. ClinVar VariationId is 330683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 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.*2426C>T		3_prime_UTR	Exon 12 of 12	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.*2426C>T		3_prime_UTR	Exon 12 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.*2426C>T		3_prime_UTR	Exon 11 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.*2426C>T		3_prime_UTR	Exon 12 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.535 AC: 80855 AN: 151102 Hom.: 26144 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.888

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.599

GnomAD4 exome AF: 0.637 AC: 274 AN: 430 Hom.: 91 Cov.: 0 AF XY: 0.615 AC XY: 160 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.639 AC: 271 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.535 AC: 80842 AN: 151216 Hom.: 26136 Cov.: 31 AF XY: 0.540 AC XY: 39921 AN XY: 73938

African (AFR) AF: 0.142 AC: 5874 AN: 41228

American (AMR) AF: 0.706 AC: 10744 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2422 AN: 3458

East Asian (EAS) AF: 0.888 AC: 4586 AN: 5164

South Asian (SAS) AF: 0.579 AC: 2768 AN: 4784

European-Finnish (FIN) AF: 0.662 AC: 6946 AN: 10492

Middle Eastern (MID) AF: 0.620 AC: 181 AN: 292

European-Non Finnish (NFE) AF: 0.673 AC: 45441 AN: 67566

Other (OTH) AF: 0.593 AC: 1247 AN: 2102

Alfa AF: 0.528 Hom.: 16058

Bravo AF: 0.525

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypohidrotic ectodermal dysplasia (1)
-	-	1	Hypohidrotic Ectodermal Dysplasia, Dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.73
PhyloP100		0.067
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: rs1478517; hg19: chr2-109510937;