chr2-108930237-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_022336.4(EDAR):c.57T>A(p.Ser19Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,074 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00075 ( 11 hom. )

Consequence

EDAR
NM_022336.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.21

Publications

2 publications found

Variant links:

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]

EDAR links:

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

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-108930237-A-T is Benign according to our data. Variant chr2-108930237-A-T is described in ClinVar as Benign. ClinVar VariationId is 532548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00718 (1093/152290) while in subpopulation AFR AF = 0.0255 (1058/41542). AF 95% confidence interval is 0.0242. There are 10 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

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.57T>A	p.Ser19Ser	synonymous	Exon 3 of 12	NP_071731.1	Q9UNE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDAR	ENST00000258443.7	TSL:1 MANE Select	c.57T>A	p.Ser19Ser	synonymous	Exon 3 of 12	ENSP00000258443.2	Q9UNE0-1
EDAR	ENST00000376651.1	TSL:2	c.57T>A	p.Ser19Ser	synonymous	Exon 3 of 11	ENSP00000365839.1	Q9UNE0-2
EDAR	ENST00000409271.5	TSL:2	c.57T>A	p.Ser19Ser	synonymous	Exon 4 of 12	ENSP00000386371.1	Q9UNE0-2

Frequencies

GnomAD3 genomes

AF:

0.00708

AC:

1078

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00189

AC:

475

AN:

251332

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.0255

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000750

AC:

1097

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

499

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0263

AC:

881

AN:

33480

American (AMR)

AF:

0.00130

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1111994

Other (OTH)

AF:

0.00180

AC:

109

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00718

AC:

1093

AN:

152290

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

532

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0255

AC:

1058

AN:

41542

American (AMR)

AF:

0.00150

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00824

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.60

(source)

DANN

Benign

0.56

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over