13-114324194-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032436.4(CHAMP1):c.352C>T(p.Pro118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHAMP1 NM_032436.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.19

Genes affected

CHAMP1 (HGNC:20311): (chromosome alignment maintaining phosphoprotein 1) This gene encodes a zinc finger protein that functions as a regulator of chromosome segregation in mitosis. The encoded protein is required for correct alignment of chromosomes on the metaphase plate, and plays a role in maintaining the attachment of sister kinetochores to microtubules from opposite spindle poles. Mutations in this gene are associated with an autosomal dominant form of intellectual disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049060613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAMP1	NM_032436.4	c.352C>T	p.Pro118Ser	missense_variant	3/3	ENST00000361283.4
CHAMP1	NM_001164144.3	c.352C>T	p.Pro118Ser	missense_variant	3/3
CHAMP1	NM_001164145.3	c.352C>T	p.Pro118Ser	missense_variant	3/3
CHAMP1	XM_047430277.1	c.352C>T	p.Pro118Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAMP1	ENST00000361283.4	c.352C>T	p.Pro118Ser	missense_variant	3/3	1	NM_032436.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.352C>T (p.P118S) alteration is located in exon 3 (coding exon 1) of the CHAMP1 gene. This alteration results from a C to T substitution at nucleotide position 352, causing the proline (P) at amino acid position 118 to be replaced by a serine (S). 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	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.35
Dann	Benign	0.37
DEOGEN2	Benign	0.11	T;T;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.049	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;.;.;.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.60	N;.;.;.;.
REVEL	Benign	0.0
Sift	Benign	0.29	T;.;.;.;.
Sift4G	Benign	0.32	T;T;.;.;.
Polyphen		0.0	B;.;.;.;B
Vest4		0.037
MutPred		0.29		Gain of catalytic residue at I117 (P = 0.0568);Gain of catalytic residue at I117 (P = 0.0568);Gain of catalytic residue at I117 (P = 0.0568);Gain of catalytic residue at I117 (P = 0.0568);Gain of catalytic residue at I117 (P = 0.0568);
MVP		0.093
MPC		0.098
ClinPred		0.032	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs2087206906; hg19: chr13-115089669;