2-108895309-A-G

Variant names:

• chr2-108895309-A-G
• rs10865025
• NM_022336.4:c.*1598T>C

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.*1598T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 152,470 control chromosomes in the GnomAD database, including 42,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (41890 hom., cov: 31)
  • Exomes 𝑓: 0.87 (165 hom.)
• Consequence: EDAR NM_022336.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.17
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-108895309-A-G is Benign according to our data. Variant chr2-108895309-A-G is described in ClinVar as Benign. ClinVar VariationId is 330688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 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.*1598T>C		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.*1598T>C		3_prime_UTR	Exon 12 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.*1598T>C		3_prime_UTR	Exon 11 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.*1598T>C		3_prime_UTR	Exon 12 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108618 AN: 151916 Hom.: 41895 Cov.: 31

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.762

GnomAD4 exome AF: 0.869 AC: 379 AN: 436 Hom.: 165 Cov.: 0 AF XY: 0.855 AC XY: 224 AN XY: 262

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: 0.869 AC: 372 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.714 AC: 108625 AN: 152034 Hom.: 41890 Cov.: 31 AF XY: 0.719 AC XY: 53434 AN XY: 74316

African (AFR) AF: 0.397 AC: 16433 AN: 41412

American (AMR) AF: 0.825 AC: 12597 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 3054 AN: 3470

East Asian (EAS) AF: 0.913 AC: 4717 AN: 5164

South Asian (SAS) AF: 0.668 AC: 3213 AN: 4812

European-Finnish (FIN) AF: 0.893 AC: 9446 AN: 10582

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.833 AC: 56642 AN: 68002

Other (OTH) AF: 0.754 AC: 1592 AN: 2112

Alfa AF: 0.753 Hom.: 10033

Bravo AF: 0.701

Asia WGS AF: 0.670 AC: 2332 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	3.3
DANN	Benign	0.78
PhyloP100		3.2
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: rs10865025; hg19: chr2-109511765;