chr2-108895011-GACTC-G

Position:

• chr2-108895011-GACTC-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_022336.4(EDAR):​c.*1892_*1895del 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.*1892_*1895del		3_prime_UTR_variant	12/12	ENST00000258443.7
EDAR	XM_006712204.2	c.*1892_*1895del		3_prime_UTR_variant	11/11
RANBP2	XM_047445367.1	c.8370+121971_8370+121974del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.*1892_*1895del		3_prime_UTR_variant	12/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.*1892_*1895del		3_prime_UTR_variant	11/11	2
EDAR	ENST00000409271.5	c.*1892_*1895del		3_prime_UTR_variant	12/12	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.0370

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0659

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.0305

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0641

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0741 Hom.: 59

Bravo AF: 0.0922

Asia WGS AF: 0.100 AC: 348 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic Ectodermal Dysplasia, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs145115545; hg19: chr2-109511467;