Genetic Variant NM_004067.4:c.1312C>T (chr7-29512640-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004067.4(CHN2):c.1312C>T(p.Pro438Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,034 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.013 ( 57 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 38 hom. )

Consequence

CHN2
NM_004067.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.667

Publications

11 publications found

Variant links:

Genes affected

CHN2 (HGNC:1944): (chimerin 2) This gene encodes a guanosine triphosphate (GTP)-metabolizing protein that contains a phorbol-ester/diacylglycerol (DAG)-type zinc finger, a Rho-GAP domain, and an SH2 domain. The encoded protein translocates from the cytosol to the Golgi apparatus membrane upon binding by diacylglycerol (DAG). Activity of this protein is important in cell proliferation and migration, and expression changes in this gene have been detected in cancers. A mutation in this gene has also been associated with schizophrenia in men. Alternative transcript splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, May 2014]

CHN2 links:

PRR15-DT (HGNC:55866): (PRR15 divergent transcript)

PRR15-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004365593).

BP6

Variant 7-29512640-C-T is Benign according to our data. Variant chr7-29512640-C-T is described in ClinVar as Benign. ClinVar VariationId is 776213.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2032/152248) while in subpopulation AFR AF = 0.0463 (1922/41532). AF 95% confidence interval is 0.0446. There are 57 homozygotes in GnomAd4. There are 973 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 57 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHN2	NM_004067.4	MANE Select	c.1312C>T	p.Pro438Ser	missense	Exon 13 of 13	NP_004058.1	P52757-1
CHN2	NM_001293070.2		c.1351C>T	p.Pro451Ser	missense	Exon 14 of 14	NP_001279999.1	B7Z1V0
CHN2	NM_001293072.2		c.1267C>T	p.Pro423Ser	missense	Exon 13 of 13	NP_001280001.1	B7Z1W9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHN2	ENST00000222792.11	TSL:1 MANE Select	c.1312C>T	p.Pro438Ser	missense	Exon 13 of 13	ENSP00000222792.7	P52757-1
CHN2	ENST00000421775.6	TSL:1	c.730C>T	p.Pro244Ser	missense	Exon 6 of 6	ENSP00000394284.2	P52757-5
CHN2	ENST00000409041.8	TSL:1	c.688C>T	p.Pro230Ser	missense	Exon 5 of 5	ENSP00000386849.5	B3VCF5

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2025

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0462

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00375

AC:

942

AN:

251260

AF XY:

0.00281

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00140

AC:

2051

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

859

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0494

AC:

1652

AN:

33474

American (AMR)

AF:

0.00327

AC:

146

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000639

AC:

AN:

1111934

Other (OTH)

AF:

0.00273

AC:

165

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

192

289

385

481

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:

0.0133

AC:

2032

AN:

152248

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

973

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0463

AC:

1922

AN:

41532

American (AMR)

AF:

0.00464

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68014

Other (OTH)

AF:

0.0133

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

189

283

378

472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00495

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0529

AC:

233

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00438

AC:

532

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CHN2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.083

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.67

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.2

REVEL

Benign

0.062

Sift

Benign

1.0

Sift4G

Benign

0.48

Polyphen

0.0010

Vest4

0.11

MVP

0.48

MPC

0.32

ClinPred

0.0036

GERP RS

4.5

Varity_R

0.31

gMVP

0.56

Mutation Taster

=91/9

polymorphism

(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