dbSNP rs3729753: NKX2-5:p.Leu202Leu (chr5-173232938-C-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004387.4(NKX2-5):c.606G>C(p.Leu202Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,605,268 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L202L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 361 hom. )

Consequence

NKX2-5
NM_004387.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.22

Publications

16 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 5-173232938-C-G is Benign according to our data. Variant chr5-173232938-C-G is described in ClinVar as Benign. ClinVar VariationId is 159256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

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.606G>C	p.Leu202Leu	synonymous	Exon 2 of 2	NP_004378.1	P52952-1
NKX2-5	NM_001166176.2		c.*405G>C		3_prime_UTR	Exon 2 of 2	NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2		c.*559G>C		3_prime_UTR	Exon 2 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.606G>C	p.Leu202Leu	synonymous	Exon 2 of 2	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2	TSL:1	c.*559G>C		3_prime_UTR	Exon 2 of 2	ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1	TSL:2	c.*405G>C		3_prime_UTR	Exon 2 of 2	ENSP00000427906.1	P52952-2

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

556

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0489

Gnomad SAS

AF:

0.0567

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00986

AC:

2250

AN:

228218

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.0000746

Gnomad AMR exome

AF:

0.0000927

Gnomad ASJ exome

AF:

0.00125

Gnomad EAS exome

AF:

0.0345

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000199

Gnomad OTH exome

AF:

0.00694

GnomAD4 exome

AF:

0.00558

AC:

8105

AN:

1452914

Hom.:

361

Cov.:

AF XY:

0.00684

AC XY:

4940

AN XY:

722352

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33360

American (AMR)

AF:

0.000208

AC:

AN:

43218

Ashkenazi Jewish (ASJ)

AF:

0.00100

AC:

AN:

25978

East Asian (EAS)

AF:

0.0819

AC:

3216

AN:

39268

South Asian (SAS)

AF:

0.0517

AC:

4431

AN:

85692

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51064

Middle Eastern (MID)

AF:

0.00266

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.0000640

AC:

AN:

1108724

Other (OTH)

AF:

0.00555

AC:

333

AN:

59966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

622

1244

1865

2487

3109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00364

AC:

555

AN:

152354

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

347

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41582

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0490

AC:

254

AN:

5180

South Asian (SAS)

AF:

0.0565

AC:

273

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68038

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000934

Hom.:

Bravo

AF:

0.00156

Asia WGS

AF:

0.0590

AC:

204

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Atrial septal defect 7 (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

2.2

Mutation Taster

=44/56

polymorphism (auto)

(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