rs921680648

Variant names:

• chrX-66599554-C-T
• rs921680648
• NM_021783.5:c.824G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-66599554-C-T
• chrX-66599554-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021783.5(EDA2R):​c.824G>A​(p.Gly275Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000929 in 1,076,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.188
• Publications: 0 publications found

Genes affected

EDA2R (HGNC:17756): (ectodysplasin A2 receptor) The protein encoded by this gene is a type III transmembrane protein of the TNFR (tumor necrosis factor receptor) superfamily, and contains cysteine-rich repeats and a single transmembrane domain. This protein binds to the EDA-A2 isoform of ectodysplasin, which plays an important role in maintenance of hair and teeth. Alternatively spliced transcript variants encodes distinct protein isoforms. [provided by RefSeq, Apr 2016]

EDA2R Gene-Disease associations (from GenCC):

• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057159126).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021783.5. 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
	EDA2R	NM_021783.5	MANE Select	c.824G>A	p.Gly275Glu	missense	Exon 6 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.887G>A	p.Gly296Glu	missense	Exon 6 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.830G>A	p.Gly277Glu	missense	Exon 6 of 7	NP_001311135.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	ENST00000374719.8	TSL:1 MANE Select	c.824G>A	p.Gly275Glu	missense	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.887G>A	p.Gly296Glu	missense	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.887G>A	p.Gly296Glu	missense	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000138 AC: 2 AN: 144700 AF XY: 0.0000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1076627 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 349577

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26012

American (AMR) AF: 0.00 AC: 0 AN: 32229

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18990

East Asian (EAS) AF: 0.0000344 AC: 1 AN: 29099

South Asian (SAS) AF: 0.00 AC: 0 AN: 51326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 830334

Other (OTH) AF: 0.00 AC: 0 AN: 45293

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.047
DANN	Benign	0.53
DEOGEN2	Benign	0.067	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.045
MutPred		0.14		Gain of solvent accessibility (P = 0.024)
MVP		0.74
ClinPred		0.010	T
GERP RS		0.83
Varity_R		0.048
gMVP		0.12
Mutation Taster		=100/0	polymorphism

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: rs921680648; hg19: chrX-65819396;