Variant 5-173232902-AGGCGGC-AGGCGGCGGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP3

The NM_004387.4(NKX2-5):c.639_641dupGCC(p.Pro214dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000523 in 1,606,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.36

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_004387.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4 linkuse as main transcript	c.639_641dupGCC	p.Pro214dup	disruptive_inframe_insertion	2/2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 linkuse as main transcript	c.438_440dupGCC		3_prime_UTR_variant	2/2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 linkuse as main transcript	c.592_594dupGCC		3_prime_UTR_variant	2/2		NP_001159647.1	P52952-3A0A0S2Z3K2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.639_641dupGCC	p.Pro214dup	disruptive_inframe_insertion	2/2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406 linkuse as main transcript	c.592_594dupGCC		3_prime_UTR_variant	2/2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848 linkuse as main transcript	c.438_440dupGCC		3_prime_UTR_variant	2/2	2		ENSP00000427906.1	P52952-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000155

AC:

AN:

218836

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

120622

show subpopulations

Gnomad AFR exome

AF:

0.000163

Gnomad AMR exome

AF:

0.000689

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000208

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000315

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000523

AC:

AN:

1454318

Hom.:

Cov.:

AF XY:

0.0000498

AC XY:

AN XY:

723164

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000595

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000763

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000294

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34374102) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 28, 2017	Found in a 14 yo female with incomplete RBBB on EKG and a history of two syncopal episodes during exercise. Her echocardiogram and cardiac MRI were read as normal. p.Pro214dup (c.639_641dupGCC) in the NKX2.5 gene (NM_004387.3) Chromosome location 5:172659912 -- / GGC Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It may be a benign ethnicity-specific variant that is more common in individuals with Latino ancestry like our patient. The NKX2.5 gene is associated with atrial septal defect with or without atrioventricular conduction defects (MedGen UID: 400040), among other things. Our patient has not shown signs of this phenotype. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. It is present, however, in population databases at an allele count that is higher than expected for a pathogenic variant. This is an in-frame insertion of a Proline amino acid amid a string of 7 Prolines. This variant was reported in at least 36 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 23 out of 15,976 Latinos (for the highest allele frequency: 0.07%), 6 South Asians, 4 non-Finnish Europeans, 2 Africans, and 1 â€œOtherâ€ ancestry individual. 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. The curators made an effort to exclude individuals with severe pediatric diseases. -

Atrial septal defect 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This variant, c.639_641dup, results in the insertion of 1 amino acid(s) of the NKX2-5 protein (p.Pro214dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777382725, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with NKX2-5-related conditions (PMID: 34374102). This variant is also known as p.P213dup. ClinVar contains an entry for this variant (Variation ID: 410968). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Tetralogy of Fallot

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

This alteration is classified as likely 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

Splicing

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