chr8-23702998-C-G

Position:

chr8-23702998-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001136271.3(NKX2-6):c.359G>C(p.Arg120Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,541,048 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 36 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 48 hom. )

Consequence

NKX2-6
NM_001136271.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.321

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029950738).

BP6

Variant 8-23702998-C-G is Benign according to our data. Variant chr8-23702998-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 466317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1796/152278) while in subpopulation AFR AF= 0.0408 (1696/41570). AF 95% confidence interval is 0.0392. There are 36 homozygotes in gnomad4. There are 827 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-6	NM_001136271.3 linkuse as main transcript	c.359G>C	p.Arg120Pro	missense_variant	2/2	ENST00000325017.4
LOC107986930	XR_001745842.2 linkuse as main transcript	n.1312+34248C>G		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.359G>C	p.Arg120Pro	missense_variant	2/2	2	NM_001136271.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1785

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0407

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

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:

0.000118

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00251

AC:

347

AN:

138096

Hom.:

AF XY:

0.00217

AC XY:

163

AN XY:

75152

show subpopulations

Gnomad AFR exome

AF:

0.0457

Gnomad AMR exome

AF:

0.00168

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:

0.000135

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00133

AC:

1854

AN:

1388770

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

839

AN XY:

684888

show subpopulations

Gnomad4 AFR exome

AF:

0.0451

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000633

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.0118

AC:

1796

AN:

152278

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

827

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0408

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.000605

Hom.:

Bravo

AF:

0.0139

ExAC

AF:

0.00128

AC:

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 03, 2023

- -

Conotruncal heart malformations

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

9.2

DANN

Benign

0.91

DEOGEN2

Benign

0.082

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.35

Sift

Benign

0.054

Sift4G

Benign

0.14

Polyphen

0.026

Vest4

0.25

MVP

0.29

MPC

0.66

ClinPred

0.026

GERP RS

3.6

Varity_R

0.23

gMVP

0.45

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