rs45594632

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001114134.2(EPB42):c.1279C>T(p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,614,094 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 19 hom. )

Consequence

EPB42
NM_001114134.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.53

Publications

7 publications found

Variant links:

Genes affected

EPB42 (HGNC:3381): (erythrocyte membrane protein band 4.2) Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of protein 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EPB42 Gene-Disease associations (from GenCC):

hereditary spherocytosis type 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary spherocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPB42 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009778529).

BP6

Variant 15-43207238-G-A is Benign according to our data. Variant chr15-43207238-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255148.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00295 (449/152224) while in subpopulation AMR AF = 0.0051 (78/15284). AF 95% confidence interval is 0.00419. There are 1 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 19 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114134.2. 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
	EPB42	NM_001114134.2	MANE Select	c.1279C>T	p.Arg427Cys	missense	Exon 9 of 13	NP_001107606.1	P16452-1
	EPB42	NM_000119.3		c.1369C>T	p.Arg457Cys	missense	Exon 9 of 13	NP_000110.2	P16452-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPB42	ENST00000441366.7	TSL:1 MANE Select	c.1279C>T	p.Arg427Cys	missense	Exon 9 of 13	ENSP00000396616.2	P16452-1
EPB42	ENST00000567019.2	TSL:1	n.785C>T		non_coding_transcript_exon	Exon 4 of 8
EPB42	ENST00000648595.1		c.1369C>T	p.Arg457Cys	missense	Exon 9 of 13	ENSP00000497777.1	P16452-2

Frequencies

GnomAD3 genomes

AF:

0.00295

AC:

449

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00447

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00292

AC:

734

AN:

251270

AF XY:

0.00286

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00476

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00487

AC:

7115

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3450

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33480

American (AMR)

AF:

0.00349

AC:

156

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00256

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000499

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00586

AC:

6519

AN:

1112006

Other (OTH)

AF:

0.00434

AC:

262

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

421

842

1264

1685

2106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.00295

AC:

449

AN:

152224

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

204

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41544

American (AMR)

AF:

0.00510

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00447

AC:

304

AN:

68012

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00400

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00272

AC:

330

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00522

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary spherocytosis type 5 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.048

Eigen_PC

Benign

0.029

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.84

M_CAP

Benign

0.015

MetaRNN

Benign

0.0098

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.13

Sift

Benign

0.073

Sift4G

Benign

0.22

Polyphen

0.46

Vest4

0.27

MVP

0.68

ClinPred

0.044

GERP RS

5.0

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.19

gMVP

0.70

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