Genetic Variant CHP2:p.Arg127Pro (chr16-23756415-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_022097.4(CHP2):c.380G>C(p.Arg127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,613,890 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 32 hom. )

Consequence

CHP2
NM_022097.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.36

Publications

5 publications found

Variant links:

Genes affected

CHP2 (HGNC:24927): (calcineurin like EF-hand protein 2) This gene product is a small calcium-binding protein that regulates cell pH by controlling plasma membrane-type Na+/H+ exchange activity. This protein shares sequence similarity with calcineurin B and can bind to and stimulate the protein phosphatase activity of calcineurin A (CnA) and functions in the calcineurin/NFAT (nuclear factor of activated T cells) signaling pathway. Another member of the CHP subfamily, Calcineurin B homologous protein 1, is located on Chromosome 15 and is an inhibitor of calcineurin activity and has a genetic phenotype associated with Parkinson's Disease (OMIM:606988). This gene was initially identified as a tumor-associated antigen and was previously referred to as Hepatocellular carcinoma-associated antigen 520. [provided by RefSeq, Jul 2013]

CHP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048438907).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1656/152156) while in subpopulation AFR AF = 0.0382 (1584/41500). AF 95% confidence interval is 0.0366. There are 25 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022097.4. 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
	CHP2	NM_022097.4	MANE Select	c.380G>C	p.Arg127Pro	missense	Exon 5 of 7	NP_071380.1	O43745

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHP2	ENST00000300113.3	TSL:1 MANE Select	c.380G>C	p.Arg127Pro	missense	Exon 5 of 7	ENSP00000300113.2	O43745
CHP2	ENST00000871596.1		c.404G>C	p.Arg135Pro	missense	Exon 5 of 7	ENSP00000541655.1
CHP2	ENST00000871595.1		c.377G>C	p.Arg126Pro	missense	Exon 5 of 7	ENSP00000541654.1

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1656

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0383

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00275

AC:

691

AN:

251262

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00109

AC:

1590

AN:

1461734

Hom.:

Cov.:

AF XY:

0.000952

AC XY:

692

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0418

AC:

1400

AN:

33464

American (AMR)

AF:

0.00123

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:

0.0000928

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111948

Other (OTH)

AF:

0.00181

AC:

109

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

148

223

297

371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0109

AC:

1656

AN:

152156

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

759

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0382

AC:

1584

AN:

41500

American (AMR)

AF:

0.00334

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68008

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

171

257

342

428

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:

0.000516

Hom.:

Bravo

AF:

0.0123

ESP6500AA

AF:

0.0401

AC:

176

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00370

AC:

449

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

2.9

PhyloP100

2.4

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.20

Sift

Uncertain

0.024

Sift4G

Benign

0.19

Polyphen

0.88

Vest4

0.62

MVP

0.80

MPC

0.70

ClinPred

0.073

GERP RS

2.9

Varity_R

0.98

gMVP

0.71

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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