Variant X-66599554-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 15/20 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.188

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057159126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5 linkuse as main transcript	c.824G>A	p.Gly275Glu	missense_variant	6/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8 linkuse as main transcript	c.824G>A	p.Gly275Glu	missense_variant	6/7	1	NM_021783.5	P1	Q9HAV5-1
EDA2R	ENST00000253392.5 linkuse as main transcript	c.887G>A	p.Gly296Glu	missense_variant	6/6	1			Q9HAV5-2
EDA2R	ENST00000396050.5 linkuse as main transcript	c.887G>A	p.Gly296Glu	missense_variant	6/7	5			Q9HAV5-2
EDA2R	ENST00000451436.6 linkuse as main transcript	c.824G>A	p.Gly275Glu	missense_variant	6/7	5		P1	Q9HAV5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000138

AC:

AN:

144700

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

43268

show subpopulations

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 SAS exome

AF:

0.00

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:

AN:

1076627

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

349577

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000344

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.887G>A (p.G296E) alteration is located in exon 6 (coding exon 6) of the EDA2R gene. This alteration results from a G to A substitution at nucleotide position 887, causing the glycine (G) at amino acid position 296 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

Cadd

Benign

0.047

Dann

Benign

0.53

DEOGEN2

Benign

0.067

T;.;T;.

FATHMM_MKL

Benign

0.013

M_CAP

Benign

0.028

MetaRNN

Benign

0.057

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.22

N;.;.;N

REVEL

Benign

0.14

Sift

Benign

0.34

T;.;.;T

Sift4G

Benign

0.40

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.045

MutPred

0.14

Gain of solvent accessibility (P = 0.024);.;Gain of solvent accessibility (P = 0.024);.;

MVP

0.74

ClinPred

0.010

GERP RS

0.83

Varity_R

0.048

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over