Genetic Variant NKX2-4:p.Lys234Asn (chr20-21396274-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_033176.2(NKX2-4):c.702G>C(p.Lys234Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NKX2-4
NM_033176.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.705

Variant links:

Genes affected

NKX2-4 (HGNC:7837): (NK2 homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NKX2-4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-4	NM_033176.2 link	c.702G>C	p.Lys234Asn	missense_variant	Exon 2 of 2	ENST00000351817.5	NP_149416.1	Q9H2Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-4	ENST00000351817.5 link	c.702G>C	p.Lys234Asn	missense_variant	Exon 2 of 2	5	NM_033176.2	ENSP00000345147.4		Q9H2Z4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454576

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32246

American (AMR)

AF:

0.00

AC:

AN:

44202

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39162

South Asian (SAS)

AF:

0.00

AC:

AN:

85358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109606

Other (OTH)

AF:

0.00

AC:

AN:

60030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.702G>C (p.K234N) alteration is located in exon 2 (coding exon 2) of the NKX2-4 gene. This alteration results from a G to C substitution at nucleotide position 702, causing the lysine (K) at amino acid position 234 to be replaced by an asparagine (N). 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

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

PhyloP100

0.70

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.72

Loss of methylation at K234 (P = 0.0012);

MVP

0.96

ClinPred

1.0

GERP RS

3.2

Varity_R

0.92

gMVP

0.76

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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20-21396274-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over