16-23757548-G-A

Variant names:

• chr16-23757548-G-A
• rs149498782
• NM_022097.4:c.556G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_022097.4(CHP2):​c.556G>A​(p.Val186Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,910 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: CHP2 NM_022097.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.244

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014960706).
• BP6: Variant 16-23757548-G-A is Benign according to our data. Variant chr16-23757548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2588851.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHP2	NM_022097.4	c.556G>A	p.Val186Ile	missense_variant	Exon 7 of 7	ENST00000300113.3	NP_071380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHP2	ENST00000300113.3	c.556G>A	p.Val186Ile	missense_variant	Exon 7 of 7	1	NM_022097.4	ENSP00000300113.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251328 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135858

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461826 Hom.: 1 Cov.: 31 AF XY: 0.000206 AC XY: 150 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74292

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 05, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.4
DANN	Benign	0.50
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.12	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.064
MVP		0.19
MPC		0.14
ClinPred		0.012	T
GERP RS		2.3
Varity_R		0.069
gMVP		0.20

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: rs149498782; hg19: chr16-23768869;