NM_022336.4:c.822C>T

Variant names:

• chr2-108908001-G-A
• rs79648056
• NM_022336.4:c.822C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_022336.4(EDAR):​c.822C>T​(p.Ser274Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,609,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. S274S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: EDAR NM_022336.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.06
• Publications: 0 publications found

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:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-3.06 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022336.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	NM_022336.4	MANE Select	c.822C>T	p.Ser274Ser	synonymous	Exon 10 of 12	NP_071731.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	ENST00000258443.7	TSL:1 MANE Select	c.822C>T	p.Ser274Ser	synonymous	Exon 10 of 12	ENSP00000258443.2
	EDAR	ENST00000376651.1	TSL:2	c.918C>T	p.Ser306Ser	synonymous	Exon 9 of 11	ENSP00000365839.1
	EDAR	ENST00000409271.5	TSL:2	c.918C>T	p.Ser306Ser	synonymous	Exon 10 of 12	ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 248352 AF XY: 0.0000149

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1457586 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 724184

African (AFR) AF: 0.0000598 AC: 2 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86192

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000271 AC: 30 AN: 1108692

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74296

African (AFR) AF: 0.000241 AC: 10 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000824 Hom.: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.36
PhyloP100		-3.1
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: rs79648056; hg19: chr2-109524457;