5-69208260-T-G

Variant names:

• chr5-69208260-T-G
• NM_022909.4:c.552T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022909.4(CENPH):​c.552T>G​(p.Ile184Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CENPH NM_022909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0860
• Publications: 0 publications found

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]

ACMG classification

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=0.11717412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4	c.552T>G	p.Ile184Met	missense_variant	Exon 8 of 9	ENST00000283006.7	NP_075060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPH	ENST00000283006.7	c.552T>G	p.Ile184Met	missense_variant	Exon 8 of 9	1	NM_022909.4	ENSP00000283006.2
CENPH	ENST00000515001.5	c.495T>G	p.Ile165Met	missense_variant	Exon 7 of 8	2		ENSP00000426014.1
CENPH	ENST00000502689.1	c.369T>G	p.Ile123Met	missense_variant	Exon 7 of 8	5		ENSP00000423936.1
CENPH	ENST00000510742.1	n.530T>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.552T>G (p.I184M) alteration is located in exon 8 (coding exon 8) of the CENPH gene. This alteration results from a T to G substitution at nucleotide position 552, causing the isoleucine (I) at amino acid position 184 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	0.062
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		0.086
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.42	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.85	P;P
Vest4		0.17
MutPred		0.27		Loss of methylation at K183 (P = 0.0231);.;
MVP		0.13
MPC		0.24
ClinPred		0.22	T
GERP RS		-5.1
Varity_R		0.043
gMVP		0.076
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr5-68504087;