chr8-23702531-C-A

Position:

chr8-23702531-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001136271.3(NKX2-6):c.826G>T(p.Ala276Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,539,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

NKX2-6
NM_001136271.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.20

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 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=0.033750743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-6	NM_001136271.3 linkuse as main transcript	c.826G>T	p.Ala276Ser	missense_variant	2/2	ENST00000325017.4
LOC107986930	XR_001745842.2 linkuse as main transcript	n.1312+33781C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-6	ENST00000325017.4 linkuse as main transcript	c.826G>T	p.Ala276Ser	missense_variant	2/2	2	NM_001136271.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000555

AC:

AN:

144048

Hom.:

AF XY:

0.0000388

AC XY:

AN XY:

77288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000163

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000584

AC:

AN:

1387136

Hom.:

Cov.:

AF XY:

0.0000527

AC XY:

AN XY:

683544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000614

Gnomad4 OTH exome

AF:

0.000122

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000471

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Conotruncal heart malformations

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 276 of the NKX2-6 protein (p.Ala276Ser). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 534673). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.075

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.084

DANN

Benign

0.82

DEOGEN2

Benign

0.043

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.35

M_CAP

Benign

0.070

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.23

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.090

REVEL

Benign

0.17

Sift

Benign

0.33

Sift4G

Benign

0.79

Polyphen

0.0010

Vest4

0.061

MutPred

0.29

Gain of glycosylation at A276 (P = 0);

MVP

0.23

MPC

0.41

ClinPred

0.040

GERP RS

-2.5

Varity_R

0.051

gMVP

0.21

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

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