rs1009994744

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004387.4(NKX2-5):​c.280C>T​(p.Pro94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

NKX2-5
NM_004387.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.77
Variant links:
Genes affected
NKX2-5 (HGNC:2488): (NK2 homeobox 5) This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.094860405).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NKX2-5NM_004387.4 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/2 ENST00000329198.5 NP_004378.1
NKX2-5NM_001166176.2 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/2 NP_001159648.1
NKX2-5NM_001166175.2 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/2 NP_001159647.1
NKX2-5XM_017009071.3 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/2 XP_016864560.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NKX2-5ENST00000329198.5 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/21 NM_004387.4 ENSP00000327758 P1P52952-1
NKX2-5ENST00000424406.2 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/21 ENSP00000395378 P52952-3
NKX2-5ENST00000521848.1 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/22 ENSP00000427906 P52952-2
NKX2-5ENST00000517440.1 linkuse as main transcriptc.280C>T p.Pro94Ser missense_variant 1/24 ENSP00000429905

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

NKX2-5-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 15, 2024The NKX2-5 c.280C>T variant is predicted to result in the amino acid substitution p.Pro94Ser. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Atrial septal defect 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 24, 2017In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NKX2-5-related disease. This sequence change replaces proline with serine at codon 94 of the NKX2-5 protein (p.Pro94Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.083
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.26
T;.;.;T
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.64
T;T;T;T
M_CAP
Uncertain
0.098
D
MetaRNN
Benign
0.095
T;T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
1.5
L;L;L;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.27
N;N;N;N
REVEL
Benign
0.23
Sift
Benign
0.43
T;T;T;T
Sift4G
Benign
0.76
T;T;T;.
Polyphen
0.0
B;.;.;B
Vest4
0.087
MutPred
0.18
Gain of phosphorylation at P94 (P = 0.0099);Gain of phosphorylation at P94 (P = 0.0099);Gain of phosphorylation at P94 (P = 0.0099);Gain of phosphorylation at P94 (P = 0.0099);
MVP
0.65
MPC
1.4
ClinPred
0.088
T
GERP RS
0.30
Varity_R
0.024
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1009994744; hg19: chr5-172661807; API