Genetic Variant NM_024111.6:c.226A>G (chr15-40953809-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024111.6(CHAC1):c.226A>G(p.Lys76Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,437,458 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: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHAC1
NM_024111.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.47

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09276447).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024111.6. 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
	CHAC1	NM_024111.6	MANE Select	c.226A>G	p.Lys76Glu	missense	Exon 1 of 3	NP_077016.3	Q9BUX1-1
	CHAC1	NM_001142776.4		c.226A>G	p.Lys76Glu	missense	Exon 1 of 4	NP_001136248.2	Q9BUX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAC1	ENST00000617768.5	TSL:1 MANE Select	c.226A>G	p.Lys76Glu	missense	Exon 1 of 3	ENSP00000484644.2	Q9BUX1-1
	CHAC1	ENST00000444189.7	TSL:1	c.226A>G	p.Lys76Glu	missense	Exon 1 of 4	ENSP00000395466.3	Q9BUX1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1437458

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33246

American (AMR)

AF:

0.00

AC:

AN:

44066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25702

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

85492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105824

Other (OTH)

AF:

0.00

AC:

AN:

59812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.83

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0081

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.99

PhyloP100

3.5

PrimateAI

Uncertain

0.59

REVEL

Benign

0.049

Sift4G

Benign

1.0

Vest4

0.16

MutPred

0.43

Loss of MoRF binding (P = 0.0107)

MVP

0.32

MPC

0.80

ClinPred

0.55

GERP RS

3.0

PromoterAI

-0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over