rs199984607

Variant names:

• chr2-108896891-C-A
• rs199984607
• NM_022336.4:c.*16G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-108896891-C-A
• chr2-108896891-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022336.4(EDAR):​c.*16G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,312 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EDAR NM_022336.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.*16G>T		3_prime_UTR	Exon 12 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.*16G>T		3_prime_UTR	Exon 12 of 12	ENSP00000258443.2
	EDAR	ENST00000376651.1	TSL:2	c.*16G>T		3_prime_UTR	Exon 11 of 11	ENSP00000365839.1
	EDAR	ENST00000409271.5	TSL:2	c.*16G>T		3_prime_UTR	Exon 12 of 12	ENSP00000386371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453312 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 722182

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 43722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 84580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108198

Other (OTH) AF: 0.0000167 AC: 1 AN: 60014

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.53
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199984607; hg19: chr2-109513347;