6-28259658-A-G

Variant names:

• chr6-28259658-A-G
• rs12000
• NM_001007531.3:c.287A>G

Variant summary

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

The NM_001007531.3(NKAPL):​c.287A>G​(p.Tyr96Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,614,060 control chromosomes in the GnomAD database, including 57,349 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 0.34 (11185 hom., cov: 33)
  • Exomes 𝑓: 0.23 (46164 hom.)
• Consequence: NKAPL NM_001007531.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 54 publications found

Genes affected

NKAPL (HGNC:21584): (NFKB activating protein like) Predicted to enable chromatin binding activity. Predicted to be involved in regulation of gene expression. Predicted to be active in nucleus. [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=1.0915858E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007531.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKAPL	NM_001007531.3	MANE Select	c.287A>G	p.Tyr96Cys	missense	Exon 1 of 1	NP_001007532.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKAPL	ENST00000343684.4	TSL:6 MANE Select	c.287A>G	p.Tyr96Cys	missense	Exon 1 of 1	ENSP00000345716.3

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51346 AN: 152104 Hom.: 11132 Cov.: 33

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.376

GnomAD2 exomes AF: 0.284 AC: 71303 AN: 251316 AF XY: 0.281

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.438

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.230 AC: 336499 AN: 1461838 Hom.: 46164 Cov.: 37 AF XY: 0.235 AC XY: 170554 AN XY: 727222

African (AFR) AF: 0.618 AC: 20700 AN: 33478

American (AMR) AF: 0.338 AC: 15132 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 9787 AN: 26136

East Asian (EAS) AF: 0.455 AC: 18057 AN: 39698

South Asian (SAS) AF: 0.399 AC: 34409 AN: 86258

European-Finnish (FIN) AF: 0.129 AC: 6908 AN: 53406

Middle Eastern (MID) AF: 0.360 AC: 2079 AN: 5768

European-Non Finnish (NFE) AF: 0.192 AC: 213002 AN: 1111978

Other (OTH) AF: 0.272 AC: 16425 AN: 60392

GnomAD4 genome AF: 0.338 AC: 51454 AN: 152222 Hom.: 11185 Cov.: 33 AF XY: 0.338 AC XY: 25161 AN XY: 74428

African (AFR) AF: 0.600 AC: 24924 AN: 41520

American (AMR) AF: 0.362 AC: 5539 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1252 AN: 3470

East Asian (EAS) AF: 0.435 AC: 2249 AN: 5166

South Asian (SAS) AF: 0.412 AC: 1989 AN: 4826

European-Finnish (FIN) AF: 0.133 AC: 1408 AN: 10612

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13021 AN: 68012

Other (OTH) AF: 0.373 AC: 788 AN: 2114

Alfa AF: 0.257 Hom.: 21514

Bravo AF: 0.366

TwinsUK AF: 0.179 AC: 664

ALSPAC AF: 0.183 AC: 707

ESP6500AA AF: 0.580 AC: 2555

ESP6500EA AF: 0.204 AC: 1757

ExAC AF: 0.286 AC: 34677

Asia WGS AF: 0.393 AC: 1363 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.9
DANN	Benign	0.75
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.74	N
PhyloP100		-0.37
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.051
Sift	Benign	0.047	D
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.055
MPC		0.54
ClinPred		0.0054	T
GERP RS		1.9
PromoterAI		-0.0084	Neutral
Varity_R		0.085
gMVP		0.10
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12000; hg19: chr6-28227436; COSMIC: COSV59197971;