chrX-66599804-C-T

Variant names:

• chrX-66599804-C-T
• rs778940212
• NM_021783.5:c.574G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021783.5(EDA2R):​c.574G>A​(p.Val192Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,206,775 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000025 (0 hom. 15 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.749
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037461728).
• BP6: Variant X-66599804-C-T is Benign according to our data. Variant chrX-66599804-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2474991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 15 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.574G>A	p.Val192Met	missense	Exon 6 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.637G>A	p.Val213Met	missense	Exon 6 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.580G>A	p.Val194Met	missense	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.574G>A	p.Val192Met	missense	Exon 6 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.637G>A	p.Val213Met	missense	Exon 6 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.637G>A	p.Val213Met	missense	Exon 6 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111474 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000514 AC: 9 AN: 175084 AF XY: 0.0000823

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000247 AC: 27 AN: 1095301 Hom.: 0 Cov.: 32 AF XY: 0.0000416 AC XY: 15 AN XY: 360953

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.0000286 AC: 1 AN: 34928

Ashkenazi Jewish (ASJ) AF: 0.0000518 AC: 1 AN: 19290

East Asian (EAS) AF: 0.00 AC: 0 AN: 30104

South Asian (SAS) AF: 0.000225 AC: 12 AN: 53347

European-Finnish (FIN) AF: 0.0000743 AC: 3 AN: 40393

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4047

European-Non Finnish (NFE) AF: 0.00000951 AC: 8 AN: 840816

Other (OTH) AF: 0.0000435 AC: 2 AN: 45987

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111474 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33670

African (AFR) AF: 0.0000327 AC: 1 AN: 30610

American (AMR) AF: 0.00 AC: 0 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3516

South Asian (SAS) AF: 0.00 AC: 0 AN: 2650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6057

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53055

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0070
DANN	Benign	0.25
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Benign	0.00088	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.75
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.24
Sift	Benign	0.44	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.091
MutPred		0.10		Loss of sheet (P = 0.0457)
MVP		0.76
ClinPred		0.015	T
GERP RS		-6.9
Varity_R		0.039
gMVP		0.077
Mutation Taster		=99/1	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: rs778940212; hg19: chrX-65819646; COSMIC: COSV104388191;