2-108894481-G-A

Position:

• chr2-108894481-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:2
• Conservation: PhyloP100: 0.0670

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:):

ACMG classification

Verdict is Benign. Variant got -14 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 id is 330683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.*2426C>T		3_prime_UTR_variant	12/12	ENST00000258443.7
EDAR	XM_006712204.2	c.*2426C>T		3_prime_UTR_variant	11/11
RANBP2	XM_047445367.1	c.8370+121435G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.*2426C>T		3_prime_UTR_variant	12/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.*2426C>T		3_prime_UTR_variant	11/11	2
EDAR	ENST00000409271.5	c.*2426C>T		3_prime_UTR_variant	12/12	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

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.706

Gnomad4 ASJ AF: 0.700

Gnomad4 EAS AF: 0.888

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.593

Alfa AF: 0.616 Hom.: 9306

Bravo AF: 0.525

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.73

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: rs1478517; hg19: chr2-109510937;