16-23757315-T-G

Variant names:

• chr16-23757315-T-G
• rs1202169650
• NM_022097.4:c.529T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022097.4(CHP2):​c.529T>G​(p.Phe177Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,482 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F177S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHP2 NM_022097.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61
• Publications: 0 publications found

Genes affected

CHP2 (HGNC:24927): (calcineurin like EF-hand protein 2) This gene product is a small calcium-binding protein that regulates cell pH by controlling plasma membrane-type Na+/H+ exchange activity. This protein shares sequence similarity with calcineurin B and can bind to and stimulate the protein phosphatase activity of calcineurin A (CnA) and functions in the calcineurin/NFAT (nuclear factor of activated T cells) signaling pathway. Another member of the CHP subfamily, Calcineurin B homologous protein 1, is located on Chromosome 15 and is an inhibitor of calcineurin activity and has a genetic phenotype associated with Parkinson's Disease (OMIM:606988). This gene was initially identified as a tumor-associated antigen and was previously referred to as Hepatocellular carcinoma-associated antigen 520. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022097.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHP2	NM_022097.4	MANE Select	c.529T>G	p.Phe177Val	missense	Exon 6 of 7	NP_071380.1	O43745

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHP2	ENST00000300113.3	TSL:1 MANE Select	c.529T>G	p.Phe177Val	missense	Exon 6 of 7	ENSP00000300113.2	O43745
	CHP2	ENST00000871596.1		c.553T>G	p.Phe185Val	missense	Exon 6 of 7	ENSP00000541655.1
	CHP2	ENST00000871595.1		c.526T>G	p.Phe176Val	missense	Exon 6 of 7	ENSP00000541654.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247852 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458482 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725148

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000225 AC: 1 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109984

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.81		Loss of stability (P = 0.0752)
MVP		0.88
MPC		0.83
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.97
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

dbSNP: rs1202169650; hg19: chr16-23768636;