8-23702764-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001136271.3(NKX2-6):c.593T>C(p.Leu198Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,554,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: NKX2-6 NM_001136271.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.14

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-6	NM_001136271.3	c.593T>C	p.Leu198Pro	missense_variant	2/2	ENST00000325017.4
LOC107986930	XR_001745842.2	n.1312+34014A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-6	ENST00000325017.4	c.593T>C	p.Leu198Pro	missense_variant	2/2	2	NM_001136271.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000990 AC: 16 AN: 161580 Hom.: 0 AF XY: 0.0000939 AC XY: 8 AN XY: 85196

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.0000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000121

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.000198 AC: 278 AN: 1402232 Hom.: 0 Cov.: 33 AF XY: 0.000198 AC XY: 137 AN XY: 691876

Gnomad4 AFR exome AF: 0.0000629

Gnomad4 AMR exome AF: 0.0000279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000121

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000223

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0000541 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Conotruncal heart malformations Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2022	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. 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. ClinVar contains an entry for this variant (Variation ID: 1513585). This variant has not been reported in the literature in individuals affected with NKX2-6-related conditions. This variant is present in population databases (rs368111443, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 198 of the NKX2-6 protein (p.Leu198Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.62
MPC		1.7
ClinPred		0.62	D
GERP RS		3.9
Varity_R		0.86
gMVP		0.66

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: rs368111443; hg19: chr8-23560277;