rs28936670

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004387.4(NKX2-5):c.73C>T(p.Arg25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,236 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0099 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 30 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1B:9

Conservation

PhyloP100: 0.972

Publications

48 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007823437).

BP6

Variant 5-173235011-G-A is Benign according to our data. Variant chr5-173235011-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9008.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00992 (1511/152326) while in subpopulation AFR AF = 0.0319 (1325/41582). AF 95% confidence interval is 0.0304. There are 23 homozygotes in GnomAd4. There are 664 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1511 AD,Unknown,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2		NP_001159647.1	P52952-3A0A0S2Z3K2
NKX2-5	XM_017009071.3 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2		XP_016864560.1	E5RH49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000329198.5 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2	2		ENSP00000427906.1	P52952-2
NKX2-5	ENST00000517440.1 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 1 of 2	4		ENSP00000429905.1	E5RH49

Frequencies

GnomAD3 genomes

AF:

0.00991

AC:

1509

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00343

AC:

832

AN:

242556

AF XY:

0.00296

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.00352

Gnomad ASJ exome

AF:

0.00618

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00201

AC:

2929

AN:

1459910

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1401

AN XY:

726278

show subpopulations

African (AFR)

AF:

0.0340

AC:

1133

AN:

33356

American (AMR)

AF:

0.00396

AC:

177

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00552

AC:

144

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000348

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52280

Middle Eastern (MID)

AF:

0.00801

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00105

AC:

1164

AN:

1111592

Other (OTH)

AF:

0.00388

AC:

234

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

163

326

489

652

815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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

AF:

0.00992

AC:

1511

AN:

152326

Hom.:

Cov.:

AF XY:

0.00891

AC XY:

664

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0319

AC:

1325

AN:

41582

American (AMR)

AF:

0.00516

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68030

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

156

233

311

389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00316

Hom.:

Bravo

AF:

0.0114

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0265

AC:

115

ESP6500EA

AF:

0.000937

AC:

ExAC

AF:

0.00371

AC:

448

Asia WGS

AF:

0.00347

AC:

AN:

3474

EpiCase

AF:

0.00169

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 21, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 31, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg25Cys in exon 1 of NKX2-5: This variant has been reported in a large number o f individuals with congenital heart disease (Akcaboy 2008, Benson 1999, DeLuca 2 010, Esposito 2009, Goli-Pereira 2010, Goldmuntz 2001, McElhinny 2003, Raunch 20 10, Stallmeyer 2010). This variant is now considered to be benign based on its h igh population frequency (2.6%) in the Black population (97/3694 chromosomes, NH LBI Exome Variant Project http://evs.gs.washington.edu/EVS/). -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial septal defect 7

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Persistent truncus arteriosus

Pathogenic:1

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hypoplastic left heart syndrome 2

Pathogenic:1

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aortic arch interruption

Pathogenic:1

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Tetralogy of Fallot

Pathogenic:1

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hypothyroidism, congenital, nongoitrous, 5

Pathogenic:1

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NKX2-5: BS1, BS2 -

Congenital heart disease

Benign:1

Jun 04, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 04, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;.;.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.39

T;T;T;T

MetaRNN

Benign

0.0078

T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.4

L;L;L;.

PhyloP100

0.97

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.0

N;D;D;D

REVEL

Uncertain

0.35

Sift

Benign

0.040

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;.

Polyphen

0.0020

B;.;.;B

Vest4

0.24

MVP

0.87

MPC

1.6

ClinPred

0.026

GERP RS

3.9

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.13

gMVP

0.42

Mutation Taster

=96/4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over