5-69189699-C-G

Variant names:

• chr5-69189699-C-G
• NM_022909.4:c.65C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022909.4(CENPH):​c.65C>G​(p.Ala22Gly) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CENPH NM_022909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0600
• 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]

ENSG00000295746 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066514075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4	c.65C>G	p.Ala22Gly	missense_variant	Exon 1 of 9	ENST00000283006.7	NP_075060.1
LOC112267932	XR_002956215.2	n.-222G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPH	ENST00000283006.7	c.65C>G	p.Ala22Gly	missense_variant	Exon 1 of 9	1	NM_022909.4	ENSP00000283006.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>G (p.A22G) alteration is located in exon 1 (coding exon 1) of the CENPH gene. This alteration results from a C to G substitution at nucleotide position 65, causing the alanine (A) at amino acid position 22 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.5
DANN	Benign	0.67
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		0.060
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.046
Sift	Benign	0.20	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;B
Vest4		0.19
MutPred		0.25		Gain of methylation at R21 (P = 0.0581);Gain of methylation at R21 (P = 0.0581);
MVP		0.28
MPC		0.064
ClinPred		0.077	T
GERP RS		-4.0
PromoterAI		-0.0075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.062
Mutation Taster		=98/2	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: chr5-68485526;