8-23702612-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001136271.3(NKX2-6):​c.745G>A​(p.Gly249Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,547,926 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 4 hom. )

Consequence

NKX2-6
NM_001136271.3 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.389
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.033712655).
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NKX2-6NM_001136271.3 linkc.745G>A p.Gly249Arg missense_variant Exon 2 of 2 ENST00000325017.4 NP_001129743.2 A6NCS4
LOC107986930XR_001745842.2 linkn.1312+33862C>T intron_variant Intron 3 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NKX2-6ENST00000325017.4 linkc.745G>A p.Gly249Arg missense_variant Exon 2 of 2 2 NM_001136271.3 ENSP00000320089.3 A6NCS4

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
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:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000249
AC:
37
AN:
148364
Hom.:
2
AF XY:
0.000378
AC XY:
30
AN XY:
79270
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 SAS exome
AF:
0.00154
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000236
GnomAD4 exome
AF:
0.0000996
AC:
139
AN:
1395788
Hom.:
4
Cov.:
32
AF XY:
0.000150
AC XY:
103
AN XY:
688376
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000398
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00169
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000186
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152138
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.000481
AC:
14
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Conotruncal heart malformations Uncertain:1
Mar 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 249 of the NKX2-6 protein (p.Gly249Arg). This variant is present in population databases (rs752427485, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NKX2-6-related conditions. ClinVar contains an entry for this variant (Variation ID: 534672). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.59
T
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.50
Sift
Uncertain
0.015
D
Sift4G
Uncertain
0.018
D
Polyphen
0.63
P
Vest4
0.37
MutPred
0.43
Gain of methylation at G249 (P = 0.0241);
MVP
0.29
MPC
1.2
ClinPred
0.12
T
GERP RS
-0.53
Varity_R
0.11
gMVP
0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752427485; hg19: chr8-23560125; API