12-48654955-G-T

Variant names:

• chr12-48654955-G-T
• rs3741628
• NM_017822.4:c.1333C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017822.4(KANSL2):​c.1333C>A​(p.Pro445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,567,610 control chromosomes in the GnomAD database, including 261,902 homozygotes. 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: 𝑓 0.52 (21645 hom., cov: 31)
  • Exomes 𝑓: 0.58 (240257 hom.)
• Consequence: KANSL2 NM_017822.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.228
• Publications: 47 publications found

Genes affected

KANSL2 (HGNC:26024): (KAT8 regulatory NSL complex subunit 2) Involved in histone H4-K16 acetylation; histone H4-K5 acetylation; and histone H4-K8 acetylation. Located in several cellular components, including actin cytoskeleton; cytosol; and nucleoplasm. Part of histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3292924E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL2	NM_017822.4	c.1333C>A	p.Pro445Thr	missense_variant	Exon 9 of 10	ENST00000420613.7	NP_060292.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL2	ENST00000420613.7	c.1333C>A	p.Pro445Thr	missense_variant	Exon 9 of 10	1	NM_017822.4	ENSP00000415436.3

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78649 AN: 151798 Hom.: 21630 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.582 AC: 107703 AN: 184960 AF XY: 0.587

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.636

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.750

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.579 AC: 819725 AN: 1415694 Hom.: 240257 Cov.: 40 AF XY: 0.583 AC XY: 408068 AN XY: 699780

African (AFR) AF: 0.319 AC: 10362 AN: 32506

American (AMR) AF: 0.631 AC: 23510 AN: 37280

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14200 AN: 25336

East Asian (EAS) AF: 0.768 AC: 28642 AN: 37306

South Asian (SAS) AF: 0.683 AC: 54683 AN: 80112

European-Finnish (FIN) AF: 0.541 AC: 27508 AN: 50834

Middle Eastern (MID) AF: 0.607 AC: 3472 AN: 5718

European-Non Finnish (NFE) AF: 0.573 AC: 623590 AN: 1087738

Other (OTH) AF: 0.573 AC: 33758 AN: 58864

GnomAD4 genome AF: 0.518 AC: 78683 AN: 151916 Hom.: 21645 Cov.: 31 AF XY: 0.522 AC XY: 38768 AN XY: 74240

African (AFR) AF: 0.331 AC: 13684 AN: 41400

American (AMR) AF: 0.581 AC: 8868 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2018 AN: 3468

East Asian (EAS) AF: 0.768 AC: 3971 AN: 5168

South Asian (SAS) AF: 0.686 AC: 3304 AN: 4816

European-Finnish (FIN) AF: 0.548 AC: 5787 AN: 10558

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39328 AN: 67942

Other (OTH) AF: 0.520 AC: 1095 AN: 2104

Alfa AF: 0.557 Hom.: 70134

Bravo AF: 0.508

TwinsUK AF: 0.575 AC: 2132

ALSPAC AF: 0.579 AC: 2233

ESP6500AA AF: 0.312 AC: 1188

ESP6500EA AF: 0.563 AC: 4639

ExAC AF: 0.518 AC: 60270

Asia WGS AF: 0.676 AC: 2349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.026	.;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;T
MetaRNN	Benign	0.0000012	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	.;L;.;.
PhyloP100		0.23
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.044	D;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T
Polyphen		0.62	P;B;.;B
Vest4		0.067
MPC		0.38
ClinPred		0.020	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.33
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3741628; hg19: chr12-49048738; COSMIC: COSV67611097; COSMIC: COSV67611097;