5-173235021-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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:12

Conservation

PhyloP100: 0.607

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 44837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173235021-T-C is described in Lovd as [Benign].

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	UniProt
NKX2-5	NM_004387.4 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2		NP_001159647.1	P52952-3A0A0S2Z3K2
NKX2-5	XM_017009071.3 link	c.63A>G	p.Glu21Glu	synonymous_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.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	2		ENSP00000427906.1	P52952-2
NKX2-5	ENST00000517440.1 link	c.63A>G	p.Glu21Glu	synonymous_variant	Exon 1 of 2	4		ENSP00000429905.1	E5RH49

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

GnomAD3 exomes

AF:

0.408

AC:

98893

AN:

242538

Hom.:

22418

AF XY:

0.394

AC XY:

52382

AN XY:

132864

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 SAS exome

AF:

0.403

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

Gnomad4 AFR exome

AF:

0.671

Gnomad4 AMR exome

AF:

0.539

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.652

Gnomad4 SAS exome

AF:

0.399

Gnomad4 FIN exome

AF:

0.425

Gnomad4 NFE exome

AF:

0.292

Gnomad4 OTH exome

AF:

0.356

GnomAD4 genome

AF:

0.440

AC:

66901

AN:

152074

Hom.:

16576

Cov.:

AF XY:

0.446

AC XY:

33180

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.660

Gnomad4 AMR

AF:

0.470

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.637

Gnomad4 SAS

AF:

0.426

Gnomad4 FIN

AF:

0.436

Gnomad4 NFE

AF:

0.294

Gnomad4 OTH

AF:

0.423

Alfa

AF:

0.360

Hom.:

8100

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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. -

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). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

DANN

Benign

0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over