10-132785002-T-C

Position:

• chr10-132785002-T-C

Variant summary

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

The ENST00000368592.8(NKX6-2):​c.748A>G​(p.Lys250Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,612,212 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: 𝑓 0.00012 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NKX6-2 ENST00000368592.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.49

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]

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=0.2062017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX6-2	NM_177400.3	c.748A>G	p.Lys250Glu	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	c.748A>G	p.Lys250Glu	missense_variant	3/3	1	NM_177400.3	ENSP00000357581	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000961 AC: 24 AN: 249744 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135568

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: 0.000601

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1460072 Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 74 AN XY: 726394

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: 0.00

Gnomad4 FIN exome AF: 0.000705

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 35 AF XY: 0.000135 AC XY: 10 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.748A>G (p.K250E) alteration is located in exon 3 (coding exon 3) of the NKX6-2 gene. This alteration results from a A to G substitution at nucleotide position 748, causing the lysine (K) at amino acid position 250 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NKX6-2-related conditions. This variant is present in population databases (rs376083581, gnomAD 0.06%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 250 of the NKX6-2 protein (p.Lys250Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.40
MVP		0.64
ClinPred		0.39	T
GERP RS		3.3
Varity_R		0.72
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs376083581; hg19: chr10-134598506;