rs606231360

Positions:

• chr5-173234821-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.262del​(p.Ala88ProfsTer88) 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: 33)
• Consequence: NKX2-5 NM_004387.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.156

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 177 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173234821-GC-G is Pathogenic according to our data. Variant chr5-173234821-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 9015.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-173234821-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.262del	p.Ala88ProfsTer88	frameshift_variant	1/2	ENST00000329198.5
NKX2-5	NM_001166176.2	c.262del	p.Ala88ProfsTer42	frameshift_variant	1/2
NKX2-5	NM_001166175.2	c.262del	p.Ala88ProfsTer77	frameshift_variant	1/2
NKX2-5	XM_017009071.3	c.262del	p.Ala88ProfsTer190	frameshift_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.262del	p.Ala88ProfsTer88	frameshift_variant	1/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.262del	p.Ala88ProfsTer77	frameshift_variant	1/2	1
NKX2-5	ENST00000521848.1	c.262del	p.Ala88ProfsTer42	frameshift_variant	1/2	2
NKX2-5	ENST00000517440.1	c.262del	p.Ala88ProfsTer?	frameshift_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

literature only

OMIM

May 15, 2005

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs606231360; hg19: chr5-172661824;