Genetic Variant ESRP2:p.Ala691Thr (chr16-68230309-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024939.3(ESRP2):c.2071G>A(p.Ala691Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,190 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A691P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 42 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 50 hom. )

Consequence

ESRP2
NM_024939.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.03

Publications

6 publications found

Variant links:

Genes affected

ESRP2 (HGNC:26152): (epithelial splicing regulatory protein 2) ESPR2 is an epithelial cell-type-specific splicing regulator (Warzecha et al., 2009 [PubMed 19285943]).[supplied by OMIM, Aug 2009]

ESRP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002219677).

BP6

Variant 16-68230309-C-T is Benign according to our data. Variant chr16-68230309-C-T is described in ClinVar as Benign. ClinVar VariationId is 780183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2011/152318) while in subpopulation AFR AF = 0.0452 (1878/41552). AF 95% confidence interval is 0.0435. There are 42 homozygotes in GnomAd4. There are 955 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2011 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024939.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRP2	NM_024939.3	MANE Select	c.2071G>A	p.Ala691Thr	missense	Exon 15 of 15	NP_079215.2
ESRP2	NM_001365264.1		c.2101G>A	p.Ala701Thr	missense	Exon 15 of 15	NP_001352193.1	Q9H6T0-1
ESRP2	NM_001365265.1		c.1905G>A	p.Pro635Pro	synonymous	Exon 14 of 14	NP_001352194.1	A0A0A1TE42

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRP2	ENST00000473183.7	TSL:1 MANE Select	c.2071G>A	p.Ala691Thr	missense	Exon 15 of 15	ENSP00000418748.2	Q9H6T0-2
ESRP2	ENST00000251366.7	TSL:1	n.2036G>A		non_coding_transcript_exon	Exon 13 of 13
ESRP2	ENST00000889115.1		c.2176G>A	p.Ala726Thr	missense	Exon 16 of 16	ENSP00000559174.1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2009

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0453

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.00343

AC:

862

AN:

251452

AF XY:

0.00250

show subpopulations

Gnomad AFR exome

AF:

0.0452

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00160

AC:

2333

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1055

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0504

AC:

1689

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000151

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000266

AC:

296

AN:

1112000

Other (OTH)

AF:

0.00328

AC:

198

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0132

AC:

2011

AN:

152318

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

955

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0452

AC:

1878

AN:

41552

American (AMR)

AF:

0.00608

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68034

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

196

293

391

489

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:

0.00384

Hom.:

Bravo

AF:

0.0155

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0444

AC:

195

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00424

AC:

515

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

ESRP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PhyloP100

3.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.010

REVEL

Benign

0.076

Sift

Benign

0.52

Sift4G

Benign

0.58

Polyphen

0.0030

Vest4

0.050

MVP

0.082

MPC

0.29

ClinPred

0.0098

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

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

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