rs576577900

Positions:

• chr8-23706478-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136271.3(NKX2-6):​c.121T>A​(p.Phe41Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,542,662 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: NKX2-6 NM_001136271.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.248

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]

LOC107986930 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021771282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-6	NM_001136271.3	c.121T>A	p.Phe41Ile	missense_variant	1/2	ENST00000325017.4	NP_001129743.2
LOC107986930	XR_001745842.2	n.1312+37728A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-6	ENST00000325017.4	c.121T>A	p.Phe41Ile	missense_variant	1/2	2	NM_001136271.3	ENSP00000320089	P1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000395 AC: 58 AN: 146998 Hom.: 1 AF XY: 0.000330 AC XY: 26 AN XY: 78758

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000237

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000880

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000926

GnomAD4 exome AF: 0.000586 AC: 815 AN: 1390356 Hom.: 0 Cov.: 35 AF XY: 0.000590 AC XY: 405 AN XY: 686054

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000723

Gnomad4 OTH exome AF: 0.000311

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74468

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000397

ExAC AF: 0.000258 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Conotruncal heart malformations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 41 of the NKX2-6 protein (p.Phe41Ile). This variant is present in population databases (rs576577900, gnomAD 0.08%), 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: 466312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NKX2-6 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.6
DANN	Benign	0.85
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.094
Sift	Benign	0.41	T
Sift4G	Benign	0.40	T
Vest4		0.17
MVP		0.45
MPC		0.66
ClinPred		0.0098	T
GERP RS		-0.11
Varity_R		0.047
gMVP		0.23

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: rs576577900; hg19: chr8-23563991;