5-173235019-T-G

Position:

chr5-173235019-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_004387.4(NKX2-5):c.65A>C(p.Gln22Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q22K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.74

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-173235020-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2		NP_001159647.1	P52952-3A0A0S2Z3K2
NKX2-5	XM_017009071.3 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2		XP_016864560.1	E5RH49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2	2		ENSP00000427906.1	P52952-2
NKX2-5	ENST00000517440.1 linkuse as main transcript	c.65A>C	p.Gln22Pro	missense_variant	1/2	4		ENSP00000429905.1	E5RH49

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243024

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133092

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459498

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 18, 2022	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 06, 2017	p.Gln22Pro ( c.65A>C) in exon 1 of the NKX2-5 gene (NM_004387.3; chr5-172662022-T-G) SCICD Classification: variant of uncertain significance based on limited data to associate this gene with disease, lack of case data and sufficiently rare. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a family with arrhythmic cardiomyopathy (DCM/ARVC). Population data: Highest MAF in Latino population: 0.002987% (gnomAD 1/16742). GnomAD overall: 1/119469 individuals. The Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Another variant at the same codon, p.Gln22Arg has been seen in gnomAD with an MAF of 0.02230% in non-Finnish Europeans (27/60546 individuals). -

Atrial septal defect 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects NKX2-5 function (PMID: 17544441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NKX2-5 protein function. ClinVar contains an entry for this variant (Variation ID: 468245). This missense change has been observed in individual(s) with Tetrology of Fallot (PMID: 14607454). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 22 of the NKX2-5 protein (p.Gln22Pro). -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 02, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2022

The p.Q22P variant (also known as c.65A>C), located in coding exon 1 of the NKX2-5 gene, results from an A to C substitution at nucleotide position 65. The glutamine at codon 22 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a congenital heart disease cohort and one study suggests that this alteration may have an impact on protein function (McElhinney DB et al. J Am Coll Cardiol, 2003 Nov;42:1650-5; Li T et al. J Mol Biol, 2007 Jul;370:976-92). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;.;.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

1.9

L;L;L;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;.

Polyphen

0.74

P;.;.;D

Vest4

0.87

MutPred

0.44

Gain of disorder (P = 0.1276);Gain of disorder (P = 0.1276);Gain of disorder (P = 0.1276);Gain of disorder (P = 0.1276);

MVP

0.90

MPC

1.4

ClinPred

0.88

GERP RS

2.3

Varity_R

0.75

gMVP

0.87

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