Genetic Variant CENPC:p.Leu341Phe (chr4-67514497-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001812.4(CENPC):c.1021C>T(p.Leu341Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,612,834 control chromosomes in the GnomAD database, including 314,991 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.63 ( 30454 hom., cov: 31)

Exomes 𝑓: 0.62 ( 284537 hom. )

Consequence

CENPC
NM_001812.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.550

Publications

32 publications found

Variant links:

Genes affected

CENPC (HGNC:1854): (centromere protein C) Centromere protein C 1 is a centromere autoantigen and a component of the inner kinetochore plate. The protein is required for maintaining proper kinetochore size and a timely transition to anaphase. A putative pseudogene exists on chromosome 12. [provided by RefSeq, Jul 2008]

CENPC 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=1.1516624E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPC	NM_001812.4 link	c.1021C>T	p.Leu341Phe	missense_variant	Exon 8 of 19	ENST00000273853.11	NP_001803.2	Q03188-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CENPC	ENST00000273853.11 link	c.1021C>T	p.Leu341Phe	missense_variant	Exon 8 of 19	1	NM_001812.4	ENSP00000273853.6	Q03188-1
CENPC	ENST00000506882.5 link	n.1021C>T		non_coding_transcript_exon_variant	Exon 8 of 20	1		ENSP00000426078.1	Q03188-2
CENPC	ENST00000510189.5 link	n.1169C>T		non_coding_transcript_exon_variant	Exon 8 of 14	1
CENPC	ENST00000513216.5 link	n.742C>T		non_coding_transcript_exon_variant	Exon 4 of 15	5		ENSP00000421234.1	H0Y8J2

Frequencies

GnomAD3 genomes

AF:

0.630

AC:

95696

AN:

151836

Hom.:

30407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.733

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.813

Gnomad SAS

AF:

0.697

Gnomad FIN

AF:

0.568

Gnomad MID

AF:

0.726

Gnomad NFE

AF:

0.598

Gnomad OTH

AF:

0.669

GnomAD2 exomes

AF:

0.659

AC:

163200

AN:

247758

AF XY:

0.655

show subpopulations

Gnomad AFR exome

AF:

0.628

Gnomad AMR exome

AF:

0.803

Gnomad ASJ exome

AF:

0.648

Gnomad EAS exome

AF:

0.818

Gnomad FIN exome

AF:

0.571

Gnomad NFE exome

AF:

0.606

Gnomad OTH exome

AF:

0.650

GnomAD4 exome

AF:

0.622

AC:

908046

AN:

1460880

Hom.:

284537

Cov.:

AF XY:

0.623

AC XY:

452499

AN XY:

726648

show subpopulations

African (AFR)

AF:

0.641

AC:

21470

AN:

33472

American (AMR)

AF:

0.794

AC:

35440

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.643

AC:

16801

AN:

26126

East Asian (EAS)

AF:

0.795

AC:

31510

AN:

39612

South Asian (SAS)

AF:

0.680

AC:

58593

AN:

86218

European-Finnish (FIN)

AF:

0.571

AC:

30455

AN:

53332

Middle Eastern (MID)

AF:

0.717

AC:

4051

AN:

5652

European-Non Finnish (NFE)

AF:

0.604

AC:

671042

AN:

1111492

Other (OTH)

AF:

0.641

AC:

38684

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

21235

42470

63706

84941

106176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18416

36832

55248

73664

92080

<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:

0.630

AC:

95791

AN:

151954

Hom.:

30454

Cov.:

AF XY:

0.635

AC XY:

47152

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.630

AC:

26112

AN:

41444

American (AMR)

AF:

0.733

AC:

11183

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

2190

AN:

3470

East Asian (EAS)

AF:

0.813

AC:

4188

AN:

5152

South Asian (SAS)

AF:

0.698

AC:

3363

AN:

4818

European-Finnish (FIN)

AF:

0.568

AC:

5995

AN:

10556

Middle Eastern (MID)

AF:

0.723

AC:

211

AN:

292

European-Non Finnish (NFE)

AF:

0.598

AC:

40626

AN:

67944

Other (OTH)

AF:

0.672

AC:

1420

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1794

3587

5381

7174

8968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.620

Hom.:

19164

Bravo

AF:

0.645

TwinsUK

AF:

0.603

AC:

2236

ALSPAC

AF:

0.609

AC:

2348

ESP6500AA

AF:

0.631

AC:

2383

ESP6500EA

AF:

0.603

AC:

4963

ExAC

AF:

0.653

AC:

78938

Asia WGS

AF:

0.771

AC:

2681

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

PhyloP100

0.55

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

REVEL

Benign

0.16

Sift

Benign

0.12

Sift4G

Benign

0.073

Polyphen

0.97

Vest4

0.019

MPC

0.083

ClinPred

0.0066

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.034

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over