X-66599776-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_021783.5(EDA2R):c.602A>G(p.Glu201Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,096,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 7 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049180835).
• BS2: High Hemizygotes in GnomAdExome at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA2R	NM_021783.5	c.602A>G	p.Glu201Gly	missense_variant	6/7	ENST00000374719.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA2R	ENST00000374719.8	c.602A>G	p.Glu201Gly	missense_variant	6/7	1	NM_021783.5	P1
EDA2R	ENST00000253392.5	c.665A>G	p.Glu222Gly	missense_variant	6/6	1
EDA2R	ENST00000396050.5	c.665A>G	p.Glu222Gly	missense_variant	6/7	5
EDA2R	ENST00000451436.6	c.602A>G	p.Glu201Gly	missense_variant	6/7	5		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000789 AC: 14 AN: 177380 Hom.: 0 AF XY: 0.0000640 AC XY: 4 AN XY: 62546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000482

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

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: 0.0000164 AC: 18 AN: 1096289 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 7 AN XY: 361831

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000456

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The c.665A>G (p.E222G) alteration is located in exon 6 (coding exon 6) of the EDA2R gene. This alteration results from a A to G substitution at nucleotide position 665, causing the glutamic acid (E) at amino acid position 222 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T;.;T;.
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N;.;.;N
REVEL	Benign	0.045
Sift	Benign	0.12	T;.;.;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.11
MutPred		0.23		Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);.;
MVP		0.15
ClinPred		0.028	T
GERP RS		0.90
Varity_R		0.082
gMVP		0.16

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: rs766939798; hg19: chrX-65819618;