Genetic Variant NM_006387.6:c.1709G>T (chr19-16525274-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006387.6(CHERP):c.1709G>T(p.Arg570Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000078 in 1,282,034 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R570H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

CHERP
NM_006387.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

Publications

0 publications found

Variant links:

Genes affected

CHERP (HGNC:16930): (calcium homeostasis endoplasmic reticulum protein) Enables transmembrane transporter binding activity. Involved in positive regulation of calcineurin-NFAT signaling cascade and release of sequestered calcium ion into cytosol. Acts upstream of or within cellular calcium ion homeostasis and negative regulation of cell population proliferation. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CHERP links:

ENSG00000141979 (HGNC:):

ENSG00000141979 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006387.6. 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
	CHERP	NM_006387.6	MANE Select	c.1709G>T	p.Arg570Leu	missense	Exon 10 of 17	NP_006378.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHERP	ENST00000546361.7	TSL:1 MANE Select	c.1709G>T	p.Arg570Leu	missense	Exon 10 of 17	ENSP00000439856.2	Q8IWX8
ENSG00000141979	ENST00000409035.1	TSL:2	n.*194-5922G>T		intron	N/A	ENSP00000386951.2	B8ZZF3
CHERP	ENST00000862402.1		c.1709G>T	p.Arg570Leu	missense	Exon 10 of 17	ENSP00000532461.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.80e-7

AC:

AN:

1282034

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

620104

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25964

American (AMR)

AF:

0.00

AC:

AN:

18308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18156

East Asian (EAS)

AF:

0.00

AC:

AN:

32340

South Asian (SAS)

AF:

0.0000165

AC:

AN:

60476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4790

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1023962

Other (OTH)

AF:

0.00

AC:

AN:

52876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.90

PhyloP100

4.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

Sift4G

Benign

0.28

Polyphen

0.96

Vest4

0.61

MutPred

0.20

Gain of catalytic residue at F571 (P = 0.282)

MVP

0.72

MPC

2.1

ClinPred

0.76

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.49

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over