2-108923457-C-T

Variant names:

• chr2-108923457-C-T
• rs748225
• NM_022336.4:c.357-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022336.4(EDAR):​c.357-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,166 control chromosomes in the GnomAD database, including 3,762 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (580 hom., cov: 33)
  • Exomes 𝑓: 0.059 (3182 hom.)
• Consequence: EDAR NM_022336.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003956
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.633
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-108923457-C-T is Benign according to our data. Variant chr2-108923457-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	NM_022336.4	MANE Select	c.357-4G>A		splice_region intron	N/A	NP_071731.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDAR	ENST00000258443.7	TSL:1 MANE Select	c.357-4G>A		splice_region intron	N/A	ENSP00000258443.2
	EDAR	ENST00000376651.1	TSL:2	c.357-4G>A		splice_region intron	N/A	ENSP00000365839.1
	EDAR	ENST00000409271.5	TSL:2	c.357-4G>A		splice_region intron	N/A	ENSP00000386371.1

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 11249 AN: 152034 Hom.: 577 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0660

GnomAD2 exomes AF: 0.0579 AC: 14547 AN: 251412 AF XY: 0.0604

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0333

Gnomad ASJ exome AF: 0.0724

Gnomad EAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0561

GnomAD4 exome AF: 0.0591 AC: 86408 AN: 1461012 Hom.: 3182 Cov.: 31 AF XY: 0.0610 AC XY: 44327 AN XY: 726856

African (AFR) AF: 0.143 AC: 4787 AN: 33450

American (AMR) AF: 0.0364 AC: 1629 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 1861 AN: 26130

East Asian (EAS) AF: 0.0631 AC: 2504 AN: 39690

South Asian (SAS) AF: 0.117 AC: 10095 AN: 86214

European-Finnish (FIN) AF: 0.0201 AC: 1073 AN: 53408

Middle Eastern (MID) AF: 0.105 AC: 604 AN: 5762

European-Non Finnish (NFE) AF: 0.0540 AC: 60033 AN: 1111276

Other (OTH) AF: 0.0633 AC: 3822 AN: 60360

GnomAD4 genome AF: 0.0741 AC: 11275 AN: 152154 Hom.: 580 Cov.: 33 AF XY: 0.0726 AC XY: 5401 AN XY: 74384

African (AFR) AF: 0.135 AC: 5608 AN: 41472

American (AMR) AF: 0.0574 AC: 877 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5182

South Asian (SAS) AF: 0.112 AC: 541 AN: 4822

European-Finnish (FIN) AF: 0.0157 AC: 167 AN: 10606

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0520 AC: 3534 AN: 68002

Other (OTH) AF: 0.0653 AC: 138 AN: 2114

Alfa AF: 0.0626 Hom.: 262

Bravo AF: 0.0767

Asia WGS AF: 0.0880 AC: 307 AN: 3478

EpiCase AF: 0.0597

EpiControl AF: 0.0607

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)
-	-	1	Hypohidrotic ectodermal dysplasia (1)
-	-	1	Hypohidrotic Ectodermal Dysplasia, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.66
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0020
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: rs748225; hg19: chr2-109539913;