rs606231358

chr5-173234862-GCCCAGCT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_004387.4(NKX2-5):c.215_221del(p.Glu72AlafsTer102) variant causes a frameshift change. 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: 3.58

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 Likely_pathogenic. Variant got 9 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 184 pathogenic variants in the truncated region.
• PP5: Variant 5-173234862-GCCCAGCT-G is Pathogenic according to our data. Variant chr5-173234862-GCCCAGCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 9012.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-173234862-GCCCAGCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.215_221del	p.Glu72AlafsTer102	frameshift_variant	1/2	ENST00000329198.5
NKX2-5	NM_001166175.2	c.215_221del	p.Glu72AlafsTer91	frameshift_variant	1/2
NKX2-5	NM_001166176.2	c.215_221del	p.Glu72AlafsTer56	frameshift_variant	1/2
NKX2-5	XM_017009071.3	c.215_221del	p.Glu72AlafsTer204	frameshift_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.215_221del	p.Glu72AlafsTer102	frameshift_variant	1/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.215_221del	p.Glu72AlafsTer91	frameshift_variant	1/2	1
NKX2-5	ENST00000517440.1	c.215_221del	p.Glu72AlafsTer?	frameshift_variant	1/2	4
NKX2-5	ENST00000521848.1	c.215_221del	p.Glu72AlafsTer56	frameshift_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Nov 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231358; hg19: chr5-172661865;