8-23702971-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001136271.3(NKX2-6):c.386C>A(p.Ala129Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 1,544,976 control chromosomes in the GnomAD database, including 957 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 65 hom., cov: 33)

Exomes 𝑓: 0.033 ( 892 hom. )

Consequence

NKX2-6
NM_001136271.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0100

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

conotruncal heart malformations
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital heart disease
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NKX2-6 links:

LOC107986930 (HGNC:):

LOC107986930 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016201437).

BP6

Variant 8-23702971-G-T is Benign according to our data. Variant chr8-23702971-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (3635/152302) while in subpopulation NFE AF = 0.0363 (2466/68020). AF 95% confidence interval is 0.0351. There are 65 homozygotes in GnomAd4. There are 1766 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-6	NM_001136271.3 link	c.386C>A	p.Ala129Glu	missense_variant	Exon 2 of 2	ENST00000325017.4	NP_001129743.2	A6NCS4
LOC107986930	XR_001745842.2 link	n.1312+34221G>T		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-6	ENST00000325017.4 link	c.386C>A	p.Ala129Glu	missense_variant	Exon 2 of 2	2	NM_001136271.3	ENSP00000320089.3		A6NCS4

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3636

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00680

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00745

Gnomad FIN

AF:

0.0505

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0362

Gnomad OTH

AF:

0.0253

GnomAD2 exomes

AF:

0.0232

AC:

3331

AN:

143370

AF XY:

0.0230

show subpopulations

Gnomad AFR exome

AF:

0.00414

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0528

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0211

GnomAD4 exome

AF:

0.0327

AC:

45480

AN:

1392674

Hom.:

892

Cov.:

AF XY:

0.0319

AC XY:

21880

AN XY:

686616

show subpopulations

African (AFR)

AF:

0.00486

AC:

153

AN:

31476

American (AMR)

AF:

0.0104

AC:

369

AN:

35558

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

349

AN:

25046

East Asian (EAS)

AF:

0.000140

AC:

AN:

35662

South Asian (SAS)

AF:

0.0125

AC:

990

AN:

78986

European-Finnish (FIN)

AF:

0.0515

AC:

2359

AN:

45780

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

5018

European-Non Finnish (NFE)

AF:

0.0368

AC:

39651

AN:

1077376

Other (OTH)

AF:

0.0270

AC:

1558

AN:

57772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2720

5439

8159

10878

13598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1508

3016

4524

6032

7540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0239

AC:

3635

AN:

152302

Hom.:

Cov.:

AF XY:

0.0237

AC XY:

1766

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00678

AC:

282

AN:

41576

American (AMR)

AF:

0.0113

AC:

173

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00746

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0505

AC:

536

AN:

10620

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0363

AC:

2466

AN:

68020

Other (OTH)

AF:

0.0250

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

185

370

556

741

926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0288

Hom.:

Bravo

AF:

0.0203

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0319

AC:

123

ExAC

AF:

0.0103

AC:

486

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Conotruncal heart malformations

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.6

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.042

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0016

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.2

PhyloP100

0.010

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.79

REVEL

Benign

0.20

Sift

Benign

0.99

Sift4G

Benign

1.0

Polyphen

0.043

Vest4

0.097

MPC

0.54

ClinPred

0.0033

GERP RS

-2.0

Varity_R

0.056

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over