Variant rs780012501 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_001136271.3(NKX2-6):c.340_348dupAACAGCGGC(p.Gly116_Asp117insAsnSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,541,020 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

NKX2-6
NM_001136271.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.113

Variant links:

Genes affected

NKX2-6 (HGNC:32940): (NK2 homeobox 6) This gene encodes a homeobox-containing protein that belongs to the NK-2 homeobox family. This protein is a vertebrate homolog of Drosophila homeobox-containing protein called 'tinman', which has been shown to be essential for development of the heart-like dorsal vessel. In conjunction with related gene, NKX2-5, this gene may play a role in both pharyngeal and cardiac embryonic development. Mutations in this gene are associated with persistent truncus arteriosus.[provided by RefSeq, Aug 2011]

NKX2-6 links:

LOC107986930 (HGNC:):

LOC107986930 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001136271.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-6	NM_001136271.3 linkuse as main transcript	c.340_348dupAACAGCGGC	p.Gly116_Asp117insAsnSerGly	conservative_inframe_insertion	2/2	ENST00000325017.4	NP_001129743.2	A6NCS4
LOC107986930	XR_001745842.2 linkuse as main transcript	n.1312+34262_1312+34270dupGCTGTTGCC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-6	ENST00000325017.4 linkuse as main transcript	c.340_348dupAACAGCGGC	p.Gly116_Asp117insAsnSerGly	conservative_inframe_insertion	2/2	2	NM_001136271.3	ENSP00000320089.3		A6NCS4

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000312

AC:

AN:

137858

Hom.:

AF XY:

0.000439

AC XY:

AN XY:

75106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000369

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00116

Gnomad FIN exome

AF:

0.0000981

Gnomad NFE exome

AF:

0.0000965

Gnomad OTH exome

AF:

0.000486

GnomAD4 exome

AF:

0.000204

AC:

283

AN:

1388700

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

172

AN XY:

685022

show subpopulations

Gnomad4 AFR exome

AF:

0.0000955

Gnomad4 AMR exome

AF:

0.000309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000987

Gnomad4 FIN exome

AF:

0.0000477

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.000312

GnomAD4 genome

AF:

0.000144

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Conotruncal heart malformations

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2022

This variant, c.340_348dup, results in the insertion of 3 amino acid(s) of the NKX2-6 protein (p.Asn114_Gly116dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs780012501, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NKX2-6-related conditions. ClinVar contains an entry for this variant (Variation ID: 466316). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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