dbSNP rs1554510734: NKX2-6:p.Gly289Gly (chr8-23702490-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001136271.3(NKX2-6):c.867C>T(p.Gly289Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000882 in 1,360,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

NKX2-6
NM_001136271.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.310

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 8-23702490-G-A is Benign according to our data. Variant chr8-23702490-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 534675.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.31 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-6	NM_001136271.3 link	c.867C>T	p.Gly289Gly	synonymous_variant	Exon 2 of 2	ENST00000325017.4	NP_001129743.2	A6NCS4
LOC107986930	XR_001745842.2 link	n.1312+33740G>A		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.867C>T	p.Gly289Gly	synonymous_variant	Exon 2 of 2	2	NM_001136271.3	ENSP00000320089.3		A6NCS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000882

AC:

AN:

1360618

Hom.:

Cov.:

AF XY:

0.00000750

AC XY:

AN XY:

666932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31012

American (AMR)

AF:

0.00

AC:

AN:

33710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23440

East Asian (EAS)

AF:

0.00

AC:

AN:

35242

South Asian (SAS)

AF:

0.00

AC:

AN:

74990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5544

European-Non Finnish (NFE)

AF:

0.0000104

AC:

AN:

1061568

Other (OTH)

AF:

0.0000177

AC:

AN:

56502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Conotruncal heart malformations

Benign:1

Oct 22, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.5

(source)

DANN

Benign

0.85

PhyloP100

-0.31

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over