rs397515399

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_004387.4(NKX2-5):c.707C>A(p.Pro236His) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,611,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 3.98

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-173232837-G-T is Pathogenic according to our data. Variant chr5-173232837-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39433.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr5-173232837-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NKX2-5	NM_004387.4 linkuse as main transcript	c.707C>A	p.Pro236His	missense_variant	2/2	ENST00000329198.5
NKX2-5	NM_001166175.2 linkuse as main transcript	c.*660C>A		3_prime_UTR_variant	2/2
NKX2-5	NM_001166176.2 linkuse as main transcript	c.*506C>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.707C>A	p.Pro236His	missense_variant	2/2	1	NM_004387.4	P1	P52952-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000417

AC:

AN:

239642

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131450

show subpopulations

Gnomad AFR exome

AF:

0.0000678

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:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459612

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726036

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00000756

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2019

Published functional studies demonstrate a damaging effect with reduced transactivation within the Pbx/Nkx2-5/p15 regulatory module for spleen development (Koss et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in a patient with isolated congenital asplenia and segregated with this phenotype in two relatives (Mahlaoui et al., 2011; Koss et al., 2012); This variant is associated with the following publications: (PMID: 20846672, 22560297) -

Familial isolated congenital asplenia

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 24, 2013

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2023

The p.P236H variant (also known as c.707C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 707. The proline at codon 236 is replaced by histidine, an amino acid with similar properties. This variant has been detected in a kindred with isolated congenital asplenia and without know congenital heart disease. Functional studies from the same group indicated this variant may impair transactivation by NKX2-5 (Koss M et al. Dev Cell, 2012 May;22:913-26). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.27

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.050

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.52

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.75

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.63

Sift

Uncertain

0.025

Sift4G

Uncertain

0.029

Polyphen

0.030

Vest4

0.78

MutPred

0.41

Loss of glycosylation at S234 (P = 0.0381);

MVP

0.97

MPC

0.97

ClinPred

0.87

GERP RS

4.4

Varity_R

0.30

gMVP

0.65

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