rs145115545

Variant names:

• chr2-108895011-GACTC-G
• rs145115545
• NM_022336.4:c.*1892_*1895delGAGT

Your query was ambiguous. Multiple possible variants found:

• chr2-108895011-GACTC-G
• chr2-108895011-GACTC-GACTCACTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_022336.4(EDAR):​c.*1892_*1895delGAGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 152,602 control chromosomes in the GnomAD database, including 817 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (817 hom., cov: 31)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: EDAR NM_022336.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.741
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 2-108895011-GACTC-G is Benign according to our data. Variant chr2-108895011-GACTC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 330686.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 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.*1892_*1895delGAGT		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.*1892_*1895delGAGT		3_prime_UTR	Exon 12 of 12	ENSP00000258443.2	Q9UNE0-1
	EDAR	ENST00000376651.1	TSL:2	c.*1892_*1895delGAGT		3_prime_UTR	Exon 11 of 11	ENSP00000365839.1	Q9UNE0-2
	EDAR	ENST00000409271.5	TSL:2	c.*1892_*1895delGAGT		3_prime_UTR	Exon 12 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13482 AN: 152072 Hom.: 813 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0731

GnomAD4 exome AF: 0.0267 AC: 11 AN: 412 Hom.: 0 AF XY: 0.0234 AC XY: 6 AN XY: 256

African (AFR) AF: 0.00 AC: 0 AN: 2

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: 0.0266 AC: 9 AN: 338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0370 AC: 2 AN: 54

Other (OTH) AF: 0.00 AC: 0 AN: 14

GnomAD4 genome AF: 0.0887 AC: 13501 AN: 152190 Hom.: 817 Cov.: 31 AF XY: 0.0868 AC XY: 6461 AN XY: 74414

African (AFR) AF: 0.161 AC: 6660 AN: 41494

American (AMR) AF: 0.0659 AC: 1009 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.0305 AC: 158 AN: 5180

South Asian (SAS) AF: 0.146 AC: 706 AN: 4822

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10594

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0641 AC: 4358 AN: 68006

Other (OTH) AF: 0.0724 AC: 153 AN: 2114

Alfa AF: 0.0741 Hom.: 59

Bravo AF: 0.0922

Asia WGS AF: 0.100 AC: 348 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypohidrotic Ectodermal Dysplasia, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.74
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: rs145115545; hg19: chr2-109511467;