rs587782929

Positions:

• chr5-173232925-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004387.4(NKX2-5):​c.618del​(p.Leu207CysfsTer25) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.142

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 11 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 46 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173232925-GC-G is Pathogenic according to our data. Variant chr5-173232925-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 156159.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-173232925-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.618del	p.Leu207CysfsTer25	frameshift_variant	2/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166175.2	c.*571del		3_prime_UTR_variant	2/2		NP_001159647.1
NKX2-5	NM_001166176.2	c.*417del		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.618del	p.Leu207CysfsTer25	frameshift_variant	2/2	1	NM_004387.4	ENSP00000327758	P1
NKX2-5	ENST00000424406.2	c.*571del		3_prime_UTR_variant	2/2	1		ENSP00000395378
NKX2-5	ENST00000521848.1	c.*417del		3_prime_UTR_variant	2/2	2		ENSP00000427906

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrial septal defect 7 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Nemer Genomics and Translation Biomedicine Lab, American University of Beirut

Jan 01, 2014

Sudden cardiac death risk with previously attributed Familial Atrial Septal defect Secundum type with progressive atrioventricular block -

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: rs587782929; hg19: chr5-172659928;