5-69208299-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022909.4(CENPH):c.591C>G(p.Ile197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CENPH
NM_022909.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.140

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08296463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4 link	c.591C>G	p.Ile197Met	missense_variant	Exon 8 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.591C>G	p.Ile197Met	missense_variant	Exon 8 of 9	1	NM_022909.4	ENSP00000283006.2	Q9H3R5
CENPH	ENST00000515001.5 link	c.534C>G	p.Ile178Met	missense_variant	Exon 7 of 8	2		ENSP00000426014.1	B3KVZ3
CENPH	ENST00000502689.1 link	c.408C>G	p.Ile136Met	missense_variant	Exon 7 of 8	5		ENSP00000423936.1	H0Y9E6
CENPH	ENST00000510742.1 link	n.569C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33132

American (AMR)

AF:

0.00

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

85794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099928

Other (OTH)

AF:

0.00

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.591C>G (p.I197M) alteration is located in exon 8 (coding exon 8) of the CENPH gene. This alteration results from a C to G substitution at nucleotide position 591, causing the isoleucine (I) at amino acid position 197 to be replaced by a methionine (M). 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

0.067

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.016

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.14

PrimateAI

Benign

0.40

PROVEAN

Benign

0.51

N;N

REVEL

Benign

0.051

Sift

Benign

0.16

T;T

Sift4G

Benign

0.095

T;T

Polyphen

0.35

B;B

Vest4

0.12

MutPred

0.25

Loss of methylation at K196 (P = 0.0355);.;

MVP

0.29

MPC

0.18

ClinPred

0.16

GERP RS

2.2

Varity_R

0.048

gMVP

0.14

Mutation Taster

=100/0

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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5-69208299-C-G

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