5-69202556-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022909.4(CENPH):c.422T>C(p.Met141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,560,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CENPH
NM_022909.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

Publications

0 publications found

Variant links:

Genes affected

CENPH (HGNC:17268): (centromere protein H) Centromere and kinetochore proteins play a critical role in centromere structure, kinetochore formation, and sister chromatid separation. The protein encoded by this gene colocalizes with inner kinetochore plate proteins CENP-A and CENP-C in both interphase and metaphase. It localizes outside of centromeric heterochromatin, where CENP-B is localized, and inside the kinetochore corona, where CENP-E is localized during prometaphase. It is thought that this protein can bind to itself, as well as to CENP-A, CENP-B or CENP-C. Multimers of the protein localize constitutively to the inner kinetochore plate and play an important role in the organization and function of the active centromere-kinetochore complex. [provided by RefSeq, Jul 2008]

CENPH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4 link	c.422T>C	p.Met141Thr	missense_variant	Exon 6 of 9	ENST00000283006.7	NP_075060.1	Q9H3R5A0A0S2Z5T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CENPH	ENST00000283006.7 link	c.422T>C	p.Met141Thr	missense_variant	Exon 6 of 9	1	NM_022909.4	ENSP00000283006.2	Q9H3R5
CENPH	ENST00000515001.5 link	c.365T>C	p.Met122Thr	missense_variant	Exon 5 of 8	2		ENSP00000426014.1	B3KVZ3
CENPH	ENST00000502689.1 link	c.239T>C	p.Met80Thr	missense_variant	Exon 5 of 8	5		ENSP00000423936.1	H0Y9E6
CENPH	ENST00000513575.5 link	n.424T>C		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000821

AC:

AN:

243516

AF XY:

0.00000759

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32260

American (AMR)

AF:

0.00

AC:

AN:

42410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25696

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39010

South Asian (SAS)

AF:

0.00

AC:

AN:

82390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068690

Other (OTH)

AF:

0.00

AC:

AN:

58564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.422T>C (p.M141T) alteration is located in exon 6 (coding exon 6) of the CENPH gene. This alteration results from a T to C substitution at nucleotide position 422, causing the methionine (M) at amino acid position 141 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.0043

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

1.5

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.98

D;P

Vest4

0.46

MutPred

0.60

Loss of stability (P = 0.0956);.;

MVP

0.80

MPC

0.14

ClinPred

0.74

GERP RS

4.7

Varity_R

0.26

gMVP

0.37

Mutation Taster

=87/13

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

5-69202556-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over