Genetic Variant NM_177400.3:c.121A>G (chr10-132785828-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_177400.3(NKX6-2):c.121A>G(p.Lys41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,231,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K41R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

NKX6-2
NM_177400.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

NKX6-2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a chain Homeobox protein Nkx-6.2 (size 276) in uniprot entity NKX62_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_177400.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39647496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX6-2	NM_177400.3 link	c.121A>G	p.Lys41Glu	missense_variant	Exon 1 of 3	ENST00000368592.8	NP_796374.2	Q9C056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX6-2	ENST00000368592.8 link	c.121A>G	p.Lys41Glu	missense_variant	Exon 1 of 3	1	NM_177400.3	ENSP00000357581.5		Q9C056

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.12e-7

AC:

AN:

1231912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608672

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25204

American (AMR)

AF:

0.00

AC:

AN:

21552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17722

East Asian (EAS)

AF:

0.00

AC:

AN:

29640

South Asian (SAS)

AF:

0.00

AC:

AN:

56214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4742

European-Non Finnish (NFE)

AF:

0.00000100

AC:

AN:

996692

Other (OTH)

AF:

0.00

AC:

AN:

48898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.22

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.40

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.4

PhyloP100

1.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.40

Sift

Benign

0.56

Sift4G

Benign

0.30

Polyphen

0.31

Vest4

0.44

MutPred

0.45

Loss of methylation at K41 (P = 0.0012);

MVP

0.76

ClinPred

0.39

GERP RS

3.1

PromoterAI

-0.081

Neutral

(source)

Varity_R

0.18

gMVP

0.51

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over