2-108894752-A-ATAAG

Position:

• chr2-108894752-A-ATAAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_022336.4(EDAR):​c.*2151_*2154dupCTTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,058 control chromosomes in the GnomAD database, including 2,771 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2771 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EDAR NM_022336.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0470

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 2-108894752-A-ATAAG is Benign according to our data. Variant chr2-108894752-A-ATAAG is described in ClinVar as [Likely_benign]. Clinvar id is 330684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.*2151_*2154dupCTTA		3_prime_UTR_variant	12/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.*2151_*2154dupCTTA		3_prime_UTR_variant	11/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+121710_8370+121713dupGTAA		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443	c.*2151_*2154dupCTTA		3_prime_UTR_variant	12/12	1	NM_022336.4	ENSP00000258443.2
EDAR	ENST00000376651	c.*2151_*2154dupCTTA		3_prime_UTR_variant	11/11	2		ENSP00000365839.1
EDAR	ENST00000409271	c.*2151_*2154dupCTTA		3_prime_UTR_variant	12/12	2		ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22001 AN: 151940 Hom.: 2754 Cov.: 30

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0883

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.116

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 36 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 28

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.145 AC: 22058 AN: 152058 Hom.: 2771 Cov.: 30 AF XY: 0.142 AC XY: 10525 AN XY: 74352

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.0882

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.0464

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0697

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0271 Hom.: 35

Asia WGS AF: 0.141 AC: 491 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic Ectodermal Dysplasia, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111463955; hg19: chr2-109511208;