3-20040557-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003884.5(KAT2B):c.80C>G(p.Pro27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,063,948 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: KAT2B NM_003884.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.207

Genes affected

KAT2B (HGNC:8638): (lysine acetyltransferase 2B) CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by this gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057283938).
• BP6: Variant 3-20040557-C-G is Benign according to our data. Variant chr3-20040557-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2347855.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT2B	NM_003884.5	c.80C>G	p.Pro27Arg	missense_variant	1/18	ENST00000263754.5
KAT2B	XM_005265528.5	c.80C>G	p.Pro27Arg	missense_variant	1/17
KAT2B	XM_047449147.1	c.-416C>G		5_prime_UTR_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT2B	ENST00000263754.5	c.80C>G	p.Pro27Arg	missense_variant	1/18	1	NM_003884.5	P1

Frequencies

GnomAD3 genomes AF: 0.000957 AC: 140 AN: 146366 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00135

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00125 AC: 1150 AN: 917474 Hom.: 1 Cov.: 29 AF XY: 0.00120 AC XY: 516 AN XY: 430008

Gnomad4 AFR exome AF: 0.000168

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.000126

Gnomad4 EAS exome AF: 0.0000982

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.000952

GnomAD4 genome AF: 0.000956 AC: 140 AN: 146474 Hom.: 0 Cov.: 31 AF XY: 0.000757 AC XY: 54 AN XY: 71312

Gnomad4 AFR AF: 0.000196

Gnomad4 AMR AF: 0.00135

Gnomad4 ASJ AF: 0.000294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.80C>G (p.P27R) alteration is located in exon 1 (coding exon 1) of the KAT2B gene. This alteration results from a C to G substitution at nucleotide position 80, causing the proline (P) at amino acid position 27 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

KAT2B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.064
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.031	D
Polyphen		0.040	B
Vest4		0.15
MVP		0.082
MPC		1.9
ClinPred		0.17	T
GERP RS		1.6
Varity_R		0.085
gMVP		0.19

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: rs1227332251; hg19: chr3-20082049; COSMIC: COSV99769399; COSMIC: COSV99769399;