Variant chr9-136011728-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_144653.5(NACC2):c.1552C>G(p.Leu518Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,382,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 7.2e-7 ( 0 hom. )

Consequence

NACC2
NM_144653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

NACC2 (HGNC:23846): (NACC family member 2) Enables several functions, including DNA-binding transcription repressor activity, RNA polymerase II-specific; histone deacetylase binding activity; and protein homodimerization activity. Involved in several processes, including negative regulation of G1/S transition of mitotic cell cycle by negative regulation of transcription from RNA polymerase II promoter; positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage; and protein homooligomerization. Located in chromatin; mitochondrion; and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

NACC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32004398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACC2	NM_144653.5 linkuse as main transcript	c.1552C>G	p.Leu518Val	missense_variant	6/6	ENST00000277554.4	NP_653254.1	Q96BF6A0A024R8I0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACC2	ENST00000277554.4 linkuse as main transcript	c.1552C>G	p.Leu518Val	missense_variant	6/6	1	NM_144653.5	ENSP00000277554.2		Q96BF6
NACC2	ENST00000371753.5 linkuse as main transcript	c.1552C>G	p.Leu518Val	missense_variant	5/5	1		ENSP00000360818.1		Q96BF6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1382416

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

679936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.32e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Dec 18, 2023

The c.1552C>G (p.L518V) alteration is located in exon 6 (coding exon 5) of the NACC2 gene. This alteration results from a C to G substitution at nucleotide position 1552, causing the leucine (L) at amino acid position 518 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

0.067

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

0.072

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.69

.;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.90

L;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.90

P;P

Vest4

0.31

MutPred

0.34

Gain of glycosylation at S519 (P = 0.0852);Gain of glycosylation at S519 (P = 0.0852);

MVP

0.76

MPC

0.87

ClinPred

0.50

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.10

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over