rs104893904

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004387.4(NKX2-5):c.61G>C(p.Glu21Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000587 in 1,612,066 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E21E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00057 ( 7 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 5.69

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009920806).

BP6

Variant 5-173235023-C-G is Benign according to our data. Variant chr5-173235023-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr5-173235023-C-G is described in Lovd as [Benign]. Variant chr5-173235023-C-G is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000575 (839/1459768) while in subpopulation MID AF= 0.00122 (7/5722). AF 95% confidence interval is 0.000574. There are 7 homozygotes in gnomad4_exome. There are 443 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NKX2-5	NM_004387.4 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2	ENST00000329198.5
NKX2-5	NM_001166176.2 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2
NKX2-5	NM_001166175.2 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2
NKX2-5	XM_017009071.3 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2	1	NM_004387.4	P1	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2	1			P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2	2			P52952-2
NKX2-5	ENST00000517440.1 linkuse as main transcript	c.61G>C	p.Glu21Gln	missense_variant	1/2	4

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00110

AC:

267

AN:

242910

Hom.:

AF XY:

0.000977

AC XY:

130

AN XY:

133046

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.0224

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000223

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.000575

AC:

839

AN:

1459768

Hom.:

Cov.:

AF XY:

0.000610

AC XY:

443

AN XY:

726232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0219

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.000703

AC:

107

AN:

152298

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.000748

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.000822

AC:

ExAC

AF:

0.000778

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000654

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NKX2-5: PP3, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	This variant is associated with the following publications: (PMID: 11714651, 17891434, 20725931, 16930004, 25274754, 25524324, 24782644, 12798584, 25333069, 25713730, 15810002, 21165553, 21110066, 20456451, 18375573, 17544441, 26805889, 27152669, 20497191, 20462343, 25944381, 14607454, 31256874, 28549997) -

Atrial septal defect 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Tetralogy of Fallot

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Nov 20, 2001

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Congenital heart disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

Oct 02, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.19

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.0099

T;T;T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.1

M;M;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.9

N;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

0.95

P;.;.;D

Vest4

0.34

MVP

0.82

MPC

1.3

ClinPred

0.053

GERP RS

4.8

Varity_R

0.33

gMVP

0.78

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