rs797045790

Variant names:

• chr5-173233064-CTG-AACGGTAC
• rs797045790
• NM_004387.4:c.478_480delCAGinsGTACCGTT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004387.4(NKX2-5):​c.478_480delCAGinsGTACCGTT​(p.Gln160ValfsTer18) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q160H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.97
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• atrial septal defect 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
• hypothyroidism, congenital, nongoitrous, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• NKX2.5-related congenital, conduction and myopathic heart disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tetralogy of fallot

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• conotruncal heart malformations

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated congenital asplenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 53 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-173233064-CTG-AACGGTAC is Pathogenic according to our data. Variant chr5-173233064-CTG-AACGGTAC is described in ClinVar as Pathogenic. ClinVar VariationId is 211670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004387.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	NM_004387.4	MANE Select	c.478_480delCAGinsGTACCGTT	p.Gln160ValfsTer18	frameshift missense	Exon 2 of 2	NP_004378.1
	NKX2-5	NM_001166176.2		c.*277_*279delCAGinsGTACCGTT		3_prime_UTR	Exon 2 of 2	NP_001159648.1
	NKX2-5	NM_001166175.2		c.*431_*433delCAGinsGTACCGTT		3_prime_UTR	Exon 2 of 2	NP_001159647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	ENST00000329198.5	TSL:1 MANE Select	c.478_480delCAGinsGTACCGTT	p.Gln160ValfsTer18	frameshift missense	Exon 2 of 2	ENSP00000327758.4
	NKX2-5	ENST00000424406.2	TSL:1	c.*431_*433delCAGinsGTACCGTT		3_prime_UTR	Exon 2 of 2	ENSP00000395378.2
	NKX2-5	ENST00000521848.1	TSL:2	c.*277_*279delCAGinsGTACCGTT		3_prime_UTR	Exon 2 of 2	ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs797045790; hg19: chr5-172660067;