5-173235021-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004387.4(NKX2-5):c.63A>G(p.Glu21Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,611,664 control chromosomes in the GnomAD database, including 104,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 16576 hom., cov: 33)

Exomes 𝑓: 0.33 ( 87838 hom. )

Consequence

NKX2-5
NM_004387.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.607

Publications

67 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 5-173235021-T-C is Benign according to our data. Variant chr5-173235021-T-C is described in ClinVar as Benign. ClinVar VariationId is 44837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.607 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NKX2-5	NM_004387.4 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2		NP_001159648.1
NKX2-5	NM_001166175.2 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2		NP_001159647.1
NKX2-5	XM_017009071.3 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NKX2-5	ENST00000329198.5 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000521848.1 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	2		ENSP00000427906.1
NKX2-5	ENST00000517440.1 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	4		ENSP00000429905.1

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

66810

AN:

151956

Hom.:

16539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.660

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.470

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.637

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.436

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.294

Gnomad OTH

AF:

0.421

GnomAD2 exomes

AF:

0.408

AC:

98893

AN:

242538

AF XY:

0.394

show subpopulations

Gnomad AFR exome

AF:

0.671

Gnomad AMR exome

AF:

0.547

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.634

Gnomad FIN exome

AF:

0.433

Gnomad NFE exome

AF:

0.297

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.332

AC:

484973

AN:

1459590

Hom.:

87838

Cov.:

AF XY:

0.332

AC XY:

241173

AN XY:

726098

show subpopulations

African (AFR)

AF:

0.671

AC:

22343

AN:

33316

American (AMR)

AF:

0.539

AC:

24080

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

8027

AN:

26070

East Asian (EAS)

AF:

0.652

AC:

25833

AN:

39634

South Asian (SAS)

AF:

0.399

AC:

34389

AN:

86152

European-Finnish (FIN)

AF:

0.425

AC:

22235

AN:

52278

Middle Eastern (MID)

AF:

0.381

AC:

2179

AN:

5716

European-Non Finnish (NFE)

AF:

0.292

AC:

324410

AN:

1111448

Other (OTH)

AF:

0.356

AC:

21477

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

18549

37097

55646

74194

92743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11162

22324

33486

44648

55810

<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:

0.440

AC:

66901

AN:

152074

Hom.:

16576

Cov.:

AF XY:

0.446

AC XY:

33180

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.660

AC:

27415

AN:

41510

American (AMR)

AF:

0.470

AC:

7197

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1067

AN:

3468

East Asian (EAS)

AF:

0.637

AC:

3268

AN:

5134

South Asian (SAS)

AF:

0.426

AC:

2052

AN:

4822

European-Finnish (FIN)

AF:

0.436

AC:

4614

AN:

10576

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.294

AC:

19960

AN:

67944

Other (OTH)

AF:

0.423

AC:

894

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1773

3546

5318

7091

8864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.391

Hom.:

11865

Bravo

AF:

0.456

Asia WGS

AF:

0.546

AC:

1895

AN:

3474

EpiCase

AF:

0.292

EpiControl

AF:

0.298

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:11

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 14, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu21Glu in exon 1 of NKX2-5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 67% (6119/9090) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs2277923).

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 23, 2013

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 28, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Atrial septal defect 7

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

May 18, 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

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.61

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=95/5

polymorphism (auto)

(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