rs550046293

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004387.4(NKX2-5):c.298C>G(p.Pro100Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,570,500 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000063 ( 3 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.16

Variant links:

Genes affected

NKX2-5 (HGNC:2488): (NK2 homeobox 5) This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NKX2-5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017605096).

BP6

Variant 5-173234786-G-C is Benign according to our data. Variant chr5-173234786-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 239929.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000628 (89/1418310) while in subpopulation SAS AF= 0.000929 (74/79634). AF 95% confidence interval is 0.000759. There are 3 homozygotes in gnomad4_exome. There are 51 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NKX2-5	NM_004387.4 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2	1	NM_004387.4	ENSP00000327758	P1	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2	1		ENSP00000395378		P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2	2		ENSP00000427906		P52952-2
NKX2-5	ENST00000517440.1 linkuse as main transcript	c.298C>G	p.Pro100Ala	missense_variant	1/2	4		ENSP00000429905

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000198

AC:

AN:

207084

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

112948

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00175

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000628

AC:

AN:

1418310

Hom.:

Cov.:

AF XY:

0.0000726

AC XY:

AN XY:

702480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000257

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrial septal defect 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.25

T;.;.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.90

L;L;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.78

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.68

T;T;T;T

Sift4G

Benign

0.82

T;T;T;.

Polyphen

0.015

B;.;.;B

Vest4

0.13

MutPred

0.17

Loss of methylation at K104 (P = 0.1058);Loss of methylation at K104 (P = 0.1058);Loss of methylation at K104 (P = 0.1058);Loss of methylation at K104 (P = 0.1058);

MVP

0.71

MPC

0.49

ClinPred

0.025

GERP RS

0.25

Varity_R

0.043

gMVP

0.23

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