rs368366482

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_004387.4(NKX2-5):c.823C>T(p.Pro275Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,456,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. P275T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.97

Publications

6 publications found

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]

NKX2-5 Gene-Disease associations (from GenCC):

atrial septal defect 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
hypothyroidism, congenital, nongoitrous, 5
Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
NKX2.5-related congenital, conduction and myopathic heart disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tetralogy of fallot
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
conotruncal heart malformations
Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial bicuspid aortic valve
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated congenital asplenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NKX2-5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27353007).

BS2

High AC in GnomAdExome4 at 12 AD,Unknown,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NKX2-5	NM_004387.4 link	c.823C>T	p.Pro275Ser	missense_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2 link	c.*622C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2 link	c.*776C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NKX2-5	ENST00000329198.5 link	c.823C>T	p.Pro275Ser	missense_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2 link	c.*776C>T		downstream_gene_variant		1		ENSP00000395378.2
NKX2-5	ENST00000521848.1 link	c.*622C>T		downstream_gene_variant		2		ENSP00000427906.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000421

AC:

AN:

237576

AF XY:

0.00000765

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:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1456032

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33382

American (AMR)

AF:

0.00

AC:

AN:

44308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

86038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1109090

Other (OTH)

AF:

0.00

AC:

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atrial septal defect 7

Uncertain:1

May 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 275 of the NKX2-5 protein (p.Pro275Ser). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1403770). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NKX2-5 protein function. 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. -

not provided

Uncertain:1

Apr 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Cardiovascular phenotype

Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.823C>T (p.P275S) alteration is located in exon 2 (coding exon 2) of the NKX2-5 gene. This alteration results from a C to T substitution at nucleotide position 823, causing the proline (P) at amino acid position 275 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.1

PhyloP100

2.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Benign

0.17

Sift4G

Benign

0.31

Polyphen

0.23

Vest4

0.21

MutPred

0.24

Gain of glycosylation at P275 (P = 0.0423);

MVP

0.70

MPC

1.3

ClinPred

0.30

GERP RS

4.2

Varity_R

0.048

gMVP

0.53

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over