rs587784067

Positions:

• chr5-173232760-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004387.4(NKX2-5):​c.783del​(p.Ala262ArgfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173232760-CG-C is Pathogenic according to our data. Variant chr5-173232760-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173232760-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.783del	p.Ala262ArgfsTer32	frameshift_variant	2/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166175.2	c.*736del		3_prime_UTR_variant	2/2		NP_001159647.1
NKX2-5	NM_001166176.2	c.*582del		3_prime_UTR_variant	2/2		NP_001159648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.783del	p.Ala262ArgfsTer32	frameshift_variant	2/2	1	NM_004387.4	ENSP00000327758	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NKX2-5-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The NKX2-5 c.783delC variant is predicted to result in a frameshift and premature protein termination (p.Ala262Argfs*32). This variant (referred to as c.959delC) was reported to segregate with disease in a family with asymptomatic Wenckebach atrioventricular block (Guntheroth et al 2012. PubMed ID: 22920929). This variant has not been reported in a large population database, indicating it is rare. Frameshift variants in NKX2-5 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Atrial septal defect 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

This sequence change creates a premature translational stop signal (p.Ala262Argfs*32) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the NKX2-5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with atrioventricular block (PMID: 22920929). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 159257). This variant disrupts the C-terminus of the NKX2-5 protein. Other variant(s) that disrupt this region (p.Cys264*, p.Tyr268*) have been observed in individuals with NKX2-5-related conditions (PMID: 12074273; Invitae). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Malformation of the heart and great vessels Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2020

Reported in four relatives from one family with Wenckebach atrioventricular block (Wenckebach periodicity), denoted as c.959delC due to the use of alternate nomenclature, three of these affected relatives were also found to have mild apical left ventricular noncompaction (Guntheroth et al., 2012); Reported in ClinVar with conflicting interpretations (ClinVar Variant ID# 159257; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 63 amino acids are replaced with 31 different amino acids and other loss-of-function variants have been reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22920929) -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587784067; hg19: chr5-172659763;