rs60454460

Positions:

• chr2-108897198-G-C
• chr2-108897198-G-T
• chr2-108897198-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000258443.7(EDAR):​c.1056C>G​(p.Cys352Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C352C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDAR ENST00000258443.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

RANBP2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 239) in uniprot entity EDAR_HUMAN there are 44 pathogenic changes around while only 7 benign (86%) in ENST00000258443.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.1056C>G	p.Cys352Trp	missense_variant	12/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.1152C>G	p.Cys384Trp	missense_variant	11/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+124152G>C		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.1056C>G	p.Cys352Trp	missense_variant	12/12	1	NM_022336.4	ENSP00000258443	P1
EDAR	ENST00000376651.1	c.1152C>G	p.Cys384Trp	missense_variant	11/11	2		ENSP00000365839
EDAR	ENST00000409271.5	c.1152C>G	p.Cys384Trp	missense_variant	12/12	2		ENSP00000386371

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	2.2e-11	P;P;P
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.74
MutPred		0.49		.;Loss of catalytic residue at L353 (P = 0.0139);.;
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.82
gMVP		0.90

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: rs12623957; hg19: chr2-109513654;