2-108895309-A-G

Position:

• chr2-108895309-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.*1598T>C		3_prime_UTR_variant	12/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.*1598T>C		3_prime_UTR_variant	11/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+122263A>G		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443	c.*1598T>C		3_prime_UTR_variant	12/12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651	c.*1598T>C		3_prime_UTR_variant	11/11	2		ENSP00000365839.1
EDAR	ENST00000409271	c.*1598T>C		3_prime_UTR_variant	12/12	2		ENSP00000386371.1

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

Gnomad4 FIN exome AF: 0.869

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 1.00

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

Gnomad4 AFR AF: 0.397

Gnomad4 AMR AF: 0.825

Gnomad4 ASJ AF: 0.880

Gnomad4 EAS AF: 0.913

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.893

Gnomad4 NFE AF: 0.833

Gnomad4 OTH AF: 0.754

Alfa AF: 0.753 Hom.: 10033

Bravo AF: 0.701

Asia WGS AF: 0.670 AC: 2332 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic Ectodermal Dysplasia, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypohidrotic ectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.3
DANN	Benign	0.78

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: rs10865025; hg19: chr2-109511765;