chrX-66599718-G-A

Variant names:

• chrX-66599718-G-A
• rs749216567
• NM_021783.5:c.660C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021783.5(EDA2R):​c.660C>T​(p.Asp220Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,207,892 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000045 (0 hom. 14 hem.)
• Consequence: EDA2R NM_021783.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.50
• Publications: 1 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-66599718-G-A is Benign according to our data. Variant chrX-66599718-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 724005.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

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.660C>T	p.Asp220Asp	synonymous	Exon 6 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.723C>T	p.Asp241Asp	synonymous	Exon 6 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.666C>T	p.Asp222Asp	synonymous	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.660C>T	p.Asp220Asp	synonymous	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.723C>T	p.Asp241Asp	synonymous	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.723C>T	p.Asp241Asp	synonymous	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes AF: 0.0000717 AC: 8 AN: 111499 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000379

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000943

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000731 AC: 13 AN: 177850 AF XY: 0.0000318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000222

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000379

Gnomad OTH exome AF: 0.000452

GnomAD4 exome AF: 0.0000447 AC: 49 AN: 1096393 Hom.: 0 Cov.: 32 AF XY: 0.0000387 AC XY: 14 AN XY: 361987

African (AFR) AF: 0.0000379 AC: 1 AN: 26385

American (AMR) AF: 0.000228 AC: 8 AN: 35077

Ashkenazi Jewish (ASJ) AF: 0.0000518 AC: 1 AN: 19318

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30087

South Asian (SAS) AF: 0.0000747 AC: 4 AN: 53572

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40415

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4121

European-Non Finnish (NFE) AF: 0.0000309 AC: 26 AN: 841388

Other (OTH) AF: 0.000109 AC: 5 AN: 46030

GnomAD4 genome AF: 0.0000717 AC: 8 AN: 111499 Hom.: 0 Cov.: 22 AF XY: 0.0000594 AC XY: 2 AN XY: 33679

African (AFR) AF: 0.0000326 AC: 1 AN: 30653

American (AMR) AF: 0.00 AC: 0 AN: 10518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.000379 AC: 1 AN: 2642

European-Finnish (FIN) AF: 0.000165 AC: 1 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000943 AC: 5 AN: 53044

Other (OTH) AF: 0.00 AC: 0 AN: 1487

Alfa AF: 0.000145 Hom.: 2

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.11
DANN	Benign	0.61
PhyloP100		-1.5
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: rs749216567; hg19: chrX-65819560; COSMIC: COSV53633218;