Genetic Variant NM_001136271.3:c.464G>C (chr8-23702893-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001136271.3(NKX2-6):c.464G>C(p.Arg155Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,403,494 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NKX2-6
NM_001136271.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09

Publications

1 publications found

Variant links:

Genes affected

NKX2-6 (HGNC:32940): (NK2 homeobox 6) This gene encodes a homeobox-containing protein that belongs to the NK-2 homeobox family. This protein is a vertebrate homolog of Drosophila homeobox-containing protein called 'tinman', which has been shown to be essential for development of the heart-like dorsal vessel. In conjunction with related gene, NKX2-5, this gene may play a role in both pharyngeal and cardiac embryonic development. Mutations in this gene are associated with persistent truncus arteriosus.[provided by RefSeq, Aug 2011]

NKX2-6 Gene-Disease associations (from GenCC):

conotruncal heart malformations
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital heart disease
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NKX2-6 links:

LOC107986930 (HGNC:):

LOC107986930 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136271.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-6	NM_001136271.3	MANE Select	c.464G>C	p.Arg155Pro	missense	Exon 2 of 2	NP_001129743.2	A6NCS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-6	ENST00000325017.4	TSL:2 MANE Select	c.464G>C	p.Arg155Pro	missense	Exon 2 of 2	ENSP00000320089.3	A6NCS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000618

AC:

AN:

161736

AF XY:

0.0000117

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000860

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1403494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31848

American (AMR)

AF:

0.00

AC:

AN:

35960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

36294

South Asian (SAS)

AF:

0.00

AC:

AN:

79542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49520

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1081458

Other (OTH)

AF:

0.00

AC:

AN:

58218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Conotruncal heart malformations (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

0.47

PhyloP100

2.1

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.57

MutPred

0.68

Loss of MoRF binding (P = 0.0053)

MVP

0.56

MPC

1.6

ClinPred

0.95

GERP RS

3.5

Varity_R

0.84

gMVP

0.74

Mutation Taster

=61/39

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over