rs387906775

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_004387.4(NKX2-5):c.175C>G(p.Pro59Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P59P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NKX2-5
NM_004387.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.69

Publications

6 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
hypothyroidism, congenital, nongoitrous, 5
Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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)
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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-173234909-G-C is Pathogenic according to our data. Variant chr5-173234909-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 30116.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.38803738). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2		NP_001159647.1	P52952-3A0A0S2Z3K2
NKX2-5	XM_017009071.3 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2		XP_016864560.1	E5RH49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000329198.5 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2	2		ENSP00000427906.1	P52952-2
NKX2-5	ENST00000517440.1 link	c.175C>G	p.Pro59Ala	missense_variant	Exon 1 of 2	4		ENSP00000429905.1	E5RH49

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33132

American (AMR)

AF:

0.00

AC:

AN:

44170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.00

AC:

AN:

85940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109524

Other (OTH)

AF:

0.00

AC:

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Ventricular septal defect 3

Pathogenic:1

Mar 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.66

T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.1

L;L;L;.

PhyloP100

4.7

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.52

N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.57

T;T;T;T

Sift4G

Benign

0.63

T;T;T;.

Polyphen

0.63

P;.;.;B

Vest4

0.70

MutPred

0.21

Loss of glycosylation at P59 (P = 0.0502);Loss of glycosylation at P59 (P = 0.0502);Loss of glycosylation at P59 (P = 0.0502);Loss of glycosylation at P59 (P = 0.0502);

MVP

0.90

MPC

1.4

ClinPred

0.69

GERP RS

4.1

PromoterAI

-0.050

Neutral

(source)

Varity_R

0.12

gMVP

0.30

Mutation Taster

=33/67

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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rs387906775

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over