Genetic Variant EDA2R:p.Asp220Glu (chrX-66599718-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021783.5(EDA2R):c.660C>A(p.Asp220Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,393 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D220D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

EDA2R
NM_021783.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.50

Publications

0 publications found

Variant links:

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

EDA2R links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08250308).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA2R	NM_021783.5	MANE Select	c.660C>A	p.Asp220Glu	missense	Exon 6 of 7	NP_068555.2	Q9HAV5-1
EDA2R	NM_001242310.1		c.723C>A	p.Asp241Glu	missense	Exon 6 of 7	NP_001229239.1	Q9HAV5
EDA2R	NM_001324206.2		c.666C>A	p.Asp222Glu	missense	Exon 6 of 7	NP_001311135.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA2R	ENST00000374719.8	TSL:1 MANE Select	c.660C>A	p.Asp220Glu	missense	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
EDA2R	ENST00000253392.5	TSL:1	c.723C>A	p.Asp241Glu	missense	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
EDA2R	ENST00000396050.5	TSL:5	c.723C>A	p.Asp241Glu	missense	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096393

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361987

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26385

American (AMR)

AF:

0.00

AC:

AN:

35077

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19318

East Asian (EAS)

AF:

0.00

AC:

AN:

30087

South Asian (SAS)

AF:

0.00

AC:

AN:

53572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40415

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841388

Other (OTH)

AF:

0.00

AC:

AN:

46030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.024

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.72

M_CAP

Benign

0.067

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.5

PhyloP100

-1.5

PrimateAI

Benign

0.36

PROVEAN

Benign

0.080

REVEL

Uncertain

0.30

Sift

Benign

0.20

Sift4G

Benign

0.49

Polyphen

0.43

Vest4

0.26

MutPred

0.10

Gain of glycosylation at T225 (P = 0.136)

MVP

0.48

ClinPred

0.64

GERP RS

-5.0

Varity_R

0.062

gMVP

0.13

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over