rs143039156

Positions:

• chr8-23702971-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0100

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 466318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-23702971-G-T is described in Lovd as [Likely_benign]. Variant chr8-23702971-G-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-6	NM_001136271.3	c.386C>A	p.Ala129Glu	missense_variant	2/2	ENST00000325017.4	NP_001129743.2
LOC107986930	XR_001745842.2	n.1312+34221G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-6	ENST00000325017.4	c.386C>A	p.Ala129Glu	missense_variant	2/2	2	NM_001136271.3	ENSP00000320089	P1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3636 AN: 152184 Hom.: 65 Cov.: 33

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

GnomAD3 exomes AF: 0.0232 AC: 3331 AN: 143370 Hom.: 75 AF XY: 0.0230 AC XY: 1775 AN XY: 77222

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 SAS exome AF: 0.0113

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.: 33 AF XY: 0.0319 AC XY: 21880 AN XY: 686616

Gnomad4 AFR exome AF: 0.00486

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0515

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0239 AC: 3635 AN: 152302 Hom.: 65 Cov.: 33 AF XY: 0.0237 AC XY: 1766 AN XY: 74470

Gnomad4 AFR AF: 0.00678

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.0505

Gnomad4 NFE AF: 0.0363

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0301 Hom.: 33

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: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 23, 2023

- -

Conotruncal heart malformations Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.6
DANN	Benign	0.92
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0016	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.20
Sift	Benign	0.99	T
Sift4G	Benign	1.0	T
Polyphen		0.043	B
Vest4		0.097
MPC		0.54
ClinPred		0.0033	T
GERP RS		-2.0
Varity_R		0.056
gMVP		0.32

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: rs143039156; hg19: chr8-23560484; COSMIC: COSV61492893; COSMIC: COSV61492893;