Genetic Variant NKX2-6:p.Ala293Val (chr8-23702479-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136271.3(NKX2-6):c.878C>T(p.Ala293Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,343,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. A293D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

NKX2-6
NM_001136271.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.03

Publications

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

NKX2-6 links:

LOC107986930 (HGNC:):

LOC107986930 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17043656).

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.878C>T	p.Ala293Val	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.878C>T	p.Ala293Val	missense	Exon 2 of 2	ENSP00000320089.3	A6NCS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000885

AC:

AN:

113054

AF XY:

0.0000168

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.45e-7

AC:

AN:

1343138

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

656094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30520

American (AMR)

AF:

0.00

AC:

AN:

31270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22356

East Asian (EAS)

AF:

0.00

AC:

AN:

35056

South Asian (SAS)

AF:

0.0000138

AC:

AN:

72464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1052744

Other (OTH)

AF:

0.00

AC:

AN:

55764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.7

PhyloP100

2.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Uncertain

0.019

Sift4G

Benign

0.16

Polyphen

0.079

Vest4

0.20

MutPred

0.51

Loss of disorder (P = 0.0434)

MVP

0.46

MPC

0.51

ClinPred

0.33

GERP RS

1.6

Varity_R

0.13

gMVP

0.25

Mutation Taster

=99/1

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