Variant 9-136011857-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144653.5(NACC2):c.1423G>A(p.Ala475Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,559,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NACC2
NM_144653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.279

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043660104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACC2	NM_144653.5 linkuse as main transcript	c.1423G>A	p.Ala475Thr	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.1423G>A	p.Ala475Thr	missense_variant	6/6	1	NM_144653.5	ENSP00000277554.2		Q96BF6
NACC2	ENST00000371753.5 linkuse as main transcript	c.1423G>A	p.Ala475Thr	missense_variant	5/5	1		ENSP00000360818.1		Q96BF6

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000592

AC:

AN:

168846

Hom.:

AF XY:

0.0000435

AC XY:

AN XY:

91992

show subpopulations

Gnomad AFR exome

AF:

0.000105

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000820

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000131

AC:

184

AN:

1407814

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

696914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000525

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000246

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000596

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000426

AC:

Asia WGS

AF:

0.000289

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

Jul 20, 2021

The c.1423G>A (p.A475T) alteration is located in exon 6 (coding exon 5) of the NACC2 gene. This alteration results from a G to A substitution at nucleotide position 1423, causing the alanine (A) at amino acid position 475 to be replaced by a threonine (T). 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

0.069

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.68

.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.33

N;N

REVEL

Benign

0.015

Sift

Benign

0.26

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.0010

B;B

Vest4

0.063

MutPred

0.40

Gain of glycosylation at A475 (P = 0.0086);Gain of glycosylation at A475 (P = 0.0086);

MVP

0.33

MPC

0.66

ClinPred

0.54

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.022

gMVP

0.18

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