rs201442000

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BS1BS2

The NM_004387.4(NKX2-5):c.65A>G(p.Gln22Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,611,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q22E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 4.74

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

atrial septal defect 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
NKX2.5-related congenital, conduction and myopathic heart disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tetralogy of fallot
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
conotruncal heart malformations
Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypothyroidism, congenital, nongoitrous, 5
Inheritance: Unknown, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial bicuspid aortic valve
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated congenital asplenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NKX2-5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_004387.4

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000286 (417/1459498) while in subpopulation NFE AF = 0.000369 (410/1111248). AF 95% confidence interval is 0.000339. There are 0 homozygotes in GnomAdExome4. There are 202 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 19 AD,SD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004387.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NKX2-5	NM_004387.4	MANE Select	c.65A>G	p.Gln22Arg	missense	Exon 1 of 2	NP_004378.1	P52952-1
NKX2-5	NM_001166176.2		c.65A>G	p.Gln22Arg	missense	Exon 1 of 2	NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2		c.65A>G	p.Gln22Arg	missense	Exon 1 of 2	NP_001159647.1	P52952-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NKX2-5	ENST00000329198.5	TSL:1 MANE Select	c.65A>G	p.Gln22Arg	missense	Exon 1 of 2	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2	TSL:1	c.65A>G	p.Gln22Arg	missense	Exon 1 of 2	ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1	TSL:2	c.65A>G	p.Gln22Arg	missense	Exon 1 of 2	ENSP00000427906.1	P52952-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000206

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000128

AC:

AN:

243024

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000286

AC:

417

AN:

1459498

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

726092

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33346

American (AMR)

AF:

0.0000224

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000369

AC:

410

AN:

1111248

Other (OTH)

AF:

0.0000829

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.000125

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41470

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68040

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000174

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Atrial septal defect 7 (2)

Cardiovascular phenotype (2)

not provided (2)

Abnormal cardiovascular system morphology (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.0065

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.59

MetaRNN

Uncertain

0.61

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.2

PhyloP100

4.7

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.65

Sift

Benign

0.13

Sift4G

Benign

0.20

Polyphen

0.015

Vest4

0.76

MVP

0.95

MPC

1.2

ClinPred

0.077

GERP RS

2.3

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.17

gMVP

0.76

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over