5-173233001-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004387.4(NKX2-5):c.543G>A(p.Gln181Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,611,374 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 61 hom. )

Consequence

NKX2-5
NM_004387.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.37

Publications

27 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 5-173233001-C-T is Benign according to our data. Variant chr5-173233001-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00601 (916/152350) while in subpopulation AMR AF = 0.0113 (173/15308). AF 95% confidence interval is 0.00993. There are 8 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 916 AD,Unknown,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4 link	c.543G>A	p.Gln181Gln	synonymous_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 link	c.*342G>A		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 link	c.*496G>A		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1	P52952-3A0A0S2Z3K2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000329198.5 link	c.543G>A	p.Gln181Gln	synonymous_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2 link	c.*496G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1 link	c.*342G>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1	P52952-2

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

918

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00689

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00748

AC:

1836

AN:

245362

AF XY:

0.00798

show subpopulations

Gnomad AFR exome

AF:

0.000770

Gnomad AMR exome

AF:

0.00742

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.00292

Gnomad NFE exome

AF:

0.00693

Gnomad OTH exome

AF:

0.00913

GnomAD4 exome

AF:

0.00647

AC:

9447

AN:

1459024

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

4968

AN XY:

725720

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33438

American (AMR)

AF:

0.00833

AC:

369

AN:

44320

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

886

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.0125

AC:

1073

AN:

86050

European-Finnish (FIN)

AF:

0.00291

AC:

153

AN:

52644

Middle Eastern (MID)

AF:

0.0216

AC:

119

AN:

5502

European-Non Finnish (NFE)

AF:

0.00564

AC:

6269

AN:

1111120

Other (OTH)

AF:

0.00888

AC:

535

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

720

1440

2160

2880

3600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.00601

AC:

916

AN:

152350

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

435

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41584

American (AMR)

AF:

0.0113

AC:

173

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.00912

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00689

AC:

469

AN:

68036

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

147

196

245

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:

0.00616

Hom.:

Bravo

AF:

0.00628

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Jul 10, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2013

Eurofins Ntd Llc (ga)

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

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 70/13004=0.53% -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:4

Dec 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22995991, 20981092, 19464101, 24376681, 27884173, 27535533) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NKX2-5: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial septal defect 7

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial septal defect

Benign:1

Jan 07, 2015

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Lissencephaly due to TUBA1A mutation

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous c.543G>A (p.Gln181=) variant in NKX2-5 has been identified in at least 2 individuals with cardiac disease (PMID: 19464101, 24376681) but has also been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for cardiac disease. -

Cardiovascular phenotype

Benign:1

May 04, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

3.4

Mutation Taster

=42/58

disease causing

(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