rs60454460

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_022336.4(EDAR):​c.1056C>A​(p.Cys352Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EDAR NM_022336.4 stop_gained
• 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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 45 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.1056C>A	p.Cys352Ter	stop_gained	12/12	ENST00000258443.7
EDAR	XM_006712204.2	c.1152C>A	p.Cys384Ter	stop_gained	11/11
RANBP2	XM_047445367.1	c.8370+124152G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.1056C>A	p.Cys352Ter	stop_gained	12/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.1152C>A	p.Cys384Ter	stop_gained	11/11	2
EDAR	ENST00000409271.5	c.1152C>A	p.Cys384Ter	stop_gained	12/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461480 Hom.: 0 Cov.: 64 AF XY: 0.00000138 AC XY: 1 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.4e-18	P;P;P
Vest4		0.58
GERP RS		3.8

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;