Genetic Variant NM_021783.5:c.824G>C (chrX-66599554-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021783.5(EDA2R):c.824G>C(p.Gly275Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,076,628 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0000019 ( 0 hom. 1 hem. )

Consequence

EDA2R
NM_021783.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.188

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: 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=0.04383591).

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.824G>C	p.Gly275Ala	missense	Exon 6 of 7	NP_068555.2	Q9HAV5-1
EDA2R	NM_001242310.1		c.887G>C	p.Gly296Ala	missense	Exon 6 of 7	NP_001229239.1	Q9HAV5
EDA2R	NM_001324206.2		c.830G>C	p.Gly277Ala	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.824G>C	p.Gly275Ala	missense	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
EDA2R	ENST00000253392.5	TSL:1	c.887G>C	p.Gly296Ala	missense	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
EDA2R	ENST00000396050.5	TSL:5	c.887G>C	p.Gly296Ala	missense	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000186

AC:

AN:

1076628

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349578

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26012

American (AMR)

AF:

0.00

AC:

AN:

32229

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18990

East Asian (EAS)

AF:

0.0000344

AC:

AN:

29099

South Asian (SAS)

AF:

0.00

AC:

AN:

51327

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39240

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

830334

Other (OTH)

AF:

0.00

AC:

AN:

45293

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.051

(source)

DANN

Benign

0.075

DEOGEN2

Benign

0.072

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.60

M_CAP

Benign

0.047

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

-0.19

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.19

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.61

Polyphen

0.010

Vest4

0.045

MutPred

0.15

Gain of sheet (P = 0.0344)

MVP

0.60

ClinPred

0.063

GERP RS

0.83

Varity_R

0.044

gMVP

0.15

Mutation Taster

=99/1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over