Variant 10-132785005-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177400.3(NKX6-2):c.745G>A(p.Glu249Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NKX6-2
NM_177400.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.40

Variant links:

Genes affected

NKX6-2 (HGNC:19321): (NK6 homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in cell differentiation; regulation of myelination; and regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including negative regulation of transcription by RNA polymerase II; neurogenesis; and neuromuscular process controlling balance. Predicted to be part of chromatin. Predicted to be active in nucleus. Implicated in spastic ataxia 8. [provided by Alliance of Genome Resources, Apr 2022]

NKX6-2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3728843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX6-2	NM_177400.3 linkuse as main transcript	c.745G>A	p.Glu249Lys	missense_variant	3/3	ENST00000368592.8	NP_796374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX6-2	ENST00000368592.8 linkuse as main transcript	c.745G>A	p.Glu249Lys	missense_variant	3/3	1	NM_177400.3	ENSP00000357581	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249726

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459870

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726302

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.745G>A (p.E249K) alteration is located in exon 3 (coding exon 3) of the NKX6-2 gene. This alteration results from a G to A substitution at nucleotide position 745, causing the glutamic acid (E) at amino acid position 249 to be replaced by a lysine (K). 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

Pathogenic

0.58

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.21

Sift

Benign

0.069

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.44

MutPred

0.30

Gain of MoRF binding (P = 0.007);

MVP

0.63

ClinPred

0.98

GERP RS

2.4

Varity_R

0.65

gMVP

0.41

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