Variant 15-40955764-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024111.6(CHAC1):c.659C>T(p.Ala220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,593,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CHAC1
NM_024111.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

Variant links:

Genes affected

CHAC1 (HGNC:28680): (ChaC glutathione specific gamma-glutamylcyclotransferase 1) This gene encodes a member of the gamma-glutamylcyclotransferase family of proteins. The encoded protein has been shown to promote neuronal differentiation by deglycination of the Notch receptor, which prevents receptor maturation and inhibits Notch signaling. This protein may also play a role in the unfolded protein response, and in regulation of glutathione levels and oxidative balance in the cell. Elevated expression of this gene may indicate increased risk of cancer recurrence among breast and ovarian cancer patients. [provided by RefSeq, Sep 2016]

CHAC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09491745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAC1	NM_024111.6 linkuse as main transcript	c.659C>T	p.Ala220Val	missense_variant	3/3	ENST00000617768.5
CHAC1	NM_001142776.4 linkuse as main transcript	c.524C>T	p.Ala175Val	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAC1	ENST00000617768.5 linkuse as main transcript	c.659C>T	p.Ala220Val	missense_variant	3/3	1	NM_024111.6	P1	Q9BUX1-1
CHAC1	ENST00000444189.7 linkuse as main transcript	c.524C>T	p.Ala175Val	missense_variant	4/4	1			Q9BUX1-2
CHAC1	ENST00000487220.1 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000691

AC:

AN:

231408

Hom.:

AF XY:

0.0000790

AC XY:

AN XY:

126654

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000888

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000650

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000214

AC:

308

AN:

1441708

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

145

AN XY:

716828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000904

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000251

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000495

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.785C>T (p.A262V) alteration is located in exon 3 (coding exon 3) of the CHAC1 gene. This alteration results from a C to T substitution at nucleotide position 785, causing the alanine (A) at amino acid position 262 to be replaced by a valine (V). 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

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.80

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.80

T;T;.;.;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.095

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.95

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.6

.;.;.;.;D

REVEL

Benign

0.054

Sift

Pathogenic

0.0

.;.;.;.;D

Sift4G

Uncertain

0.017

.;.;D;.;D

Vest4

0.21, 0.10

MVP

0.42

MPC

0.57

ClinPred

0.081

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over