rs752427485
Positions:
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
NM_001136271.3 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: -0.389
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]
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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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NKX2-6 | NM_001136271.3 | c.745G>A | p.Gly249Arg | missense_variant | 2/2 | ENST00000325017.4 | |
LOC107986930 | XR_001745842.2 | n.1312+33862C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NKX2-6 | ENST00000325017.4 | c.745G>A | p.Gly249Arg | missense_variant | 2/2 | 2 | NM_001136271.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000249 AC: 37AN: 148364Hom.: 2 AF XY: 0.000378 AC XY: 30AN XY: 79270
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GnomAD4 exome AF: 0.0000996 AC: 139AN: 1395788Hom.: 4 Cov.: 32 AF XY: 0.000150 AC XY: 103AN XY: 688376
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Conotruncal heart malformations Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2022 | 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. 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"). ClinVar contains an entry for this variant (Variation ID: 534672). This variant has not been reported in the literature in individuals affected with NKX2-6-related conditions. This variant is present in population databases (rs752427485, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of methylation at G249 (P = 0.0241);
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at