9-136011872-T-G

Position:

• chr9-136011872-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144653.5(NACC2):​c.1408A>C​(p.Met470Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,415,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NACC2 NM_144653.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

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]

ACMG classification

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=0.17311037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NACC2	NM_144653.5	c.1408A>C	p.Met470Leu	missense_variant	6/6	ENST00000277554.4	NP_653254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NACC2	ENST00000277554.4	c.1408A>C	p.Met470Leu	missense_variant	6/6	1	NM_144653.5	ENSP00000277554.2
NACC2	ENST00000371753.5	c.1408A>C	p.Met470Leu	missense_variant	5/5	1		ENSP00000360818.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000155 AC: 22 AN: 1415924 Hom.: 0 Cov.: 34 AF XY: 0.0000200 AC XY: 14 AN XY: 701576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000259

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: 0.0000174

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.1408A>C (p.M470L) alteration is located in exon 6 (coding exon 5) of the NACC2 gene. This alteration results from a A to C substitution at nucleotide position 1408, causing the methionine (M) at amino acid position 470 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.20
Sift	Benign	0.20	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0090	B;B
Vest4		0.31
MutPred		0.30		Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);
MVP		0.66
MPC		0.64
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.29

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

Other links and lift over

dbSNP: rs981041104; hg19: chr9-138903718;