5-69191800-G-C

Variant names:

• chr5-69191800-G-C
• NM_022909.4:c.140G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022909.4(CENPH):​c.140G>C​(p.Arg47Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CENPH NM_022909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4	c.140G>C	p.Arg47Thr	missense_variant	Exon 2 of 9	ENST00000283006.7	NP_075060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPH	ENST00000283006.7	c.140G>C	p.Arg47Thr	missense_variant	Exon 2 of 9	1	NM_022909.4	ENSP00000283006.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399154 Hom.: 0 Cov.: 24 AF XY: 0.00000143 AC XY: 1 AN XY: 700184

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32148

American (AMR) AF: 0.00 AC: 0 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 39282

South Asian (SAS) AF: 0.00 AC: 0 AN: 84802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1055816

Other (OTH) AF: 0.00 AC: 0 AN: 58148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.004005), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140G>C (p.R47T) alteration is located in exon 2 (coding exon 2) of the CENPH gene. This alteration results from a G to C substitution at nucleotide position 140, causing the arginine (R) at amino acid position 47 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.099
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		2.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.28
Sift	Benign	0.066	T;T
Sift4G	Uncertain	0.017	D;D
Polyphen		0.96	D;P
Vest4		0.61
MutPred		0.89		Gain of ubiquitination at K51 (P = 0.0295);Gain of ubiquitination at K51 (P = 0.0295);
MVP		0.62
MPC		0.21
ClinPred		0.96	D
GERP RS		3.2
Varity_R		0.11
gMVP		0.39
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-68487627; COSMIC: COSV51584189; COSMIC: COSV51584189;