5-173233371-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001166176.2(NKX2-5):c.428G>A(p.Arg143Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,536,904 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 6 hom. )

Consequence

NKX2-5
NM_001166176.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0570

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 -18 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity NKX25_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_001166176.2

BP4

Computational evidence support a benign effect (MetaRNN=0.013406545).

BP6

Variant 5-173233371-C-T is Benign according to our data. Variant chr5-173233371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 190833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173233371-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00122 (186/152100) while in subpopulation SAS AF= 0.00208 (10/4806). AF 95% confidence interval is 0.00162. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4 link	c.335-162G>A		intron_variant	Intron 1 of 1	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 link	c.428G>A	p.Arg143Gln	missense_variant	Exon 2 of 2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 link	c.*126G>A		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1	P52952-3A0A0S2Z3K2
NKX2-5	XM_017009071.3 link	c.*675G>A		downstream_gene_variant			XP_016864560.1	E5RH49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000424406 link	c.*126G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000329198.5 link	c.335-162G>A		intron_variant	Intron 1 of 1	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000521848.1 link	c.428G>A	p.Arg143Gln	missense_variant	Exon 2 of 2	2		ENSP00000427906.1	P52952-2

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00127

AC:

177

AN:

139470

Hom.:

AF XY:

0.00128

AC XY:

AN XY:

74830

show subpopulations

Gnomad AFR exome

AF:

0.000658

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00192

AC:

2655

AN:

1384804

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1329

AN XY:

683336

show subpopulations

Gnomad4 AFR exome

AF:

0.000475

Gnomad4 AMR exome

AF:

0.00126

Gnomad4 ASJ exome

AF:

0.0000794

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.000258

Gnomad4 NFE exome

AF:

0.00222

Gnomad4 OTH exome

AF:

0.00181

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152100

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00234

AC:

ExAC

AF:

0.000515

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NKX2-5: BP4, BS1 -

Mar 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27373559, 26334177, 25500235) -

NKX2-5-related disorder

Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atrial septal defect 7

Benign:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C2673630:Hypothyroidism, congenital, nongoitrous, 5;C3276096:Atrial septal defect 7;C3280785:Ventricular septal defect 3;C3280795:Hypoplastic left heart syndrome 2

Benign:1

Feb 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

3.7

DANN

Benign

0.84

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.51

M_CAP

Benign

0.023

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.56

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Vest4

0.13

MVP

0.50

ClinPred

0.021

GERP RS

-2.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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