5-173234847-C-G

Position:

chr5-173234847-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004387.4(NKX2-5):c.237G>C(p.Pro79Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,588,730 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

NKX2-5
NM_004387.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.72

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 5-173234847-C-G is Benign according to our data. Variant chr5-173234847-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 36657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-173234847-C-G is described in Lovd as [Likely_benign]. Variant chr5-173234847-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.72 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00112 (170/152328) while in subpopulation NFE AF= 0.00156 (106/68036). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2	ENST00000329198.5	NP_004378.1	P52952-1A0A0S2Z383
NKX2-5	NM_001166176.2 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2		NP_001159648.1	P52952-2
NKX2-5	NM_001166175.2 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2		NP_001159647.1	P52952-3A0A0S2Z3K2
NKX2-5	XM_017009071.3 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2		XP_016864560.1	E5RH49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NKX2-5	ENST00000329198.5 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2	1	NM_004387.4	ENSP00000327758.4	P52952-1
NKX2-5	ENST00000424406.2 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2	1		ENSP00000395378.2	P52952-3
NKX2-5	ENST00000521848.1 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2	2		ENSP00000427906.1	P52952-2
NKX2-5	ENST00000517440.1 linkuse as main transcript	c.237G>C	p.Pro79Pro	synonymous_variant	1/2	4		ENSP00000429905.1	E5RH49

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

170

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00105

AC:

229

AN:

217988

Hom.:

AF XY:

0.00109

AC XY:

131

AN XY:

120144

show subpopulations

Gnomad AFR exome

AF:

0.000534

Gnomad AMR exome

AF:

0.000700

Gnomad ASJ exome

AF:

0.00525

Gnomad EAS exome

AF:

0.000367

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000152

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.000770

GnomAD4 exome

AF:

0.00134

AC:

1928

AN:

1436402

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

938

AN XY:

713190

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000594

Gnomad4 ASJ exome

AF:

0.00595

Gnomad4 EAS exome

AF:

0.000620

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.000135

Gnomad4 NFE exome

AF:

0.00146

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00112

AC:

170

AN:

152328

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00130

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Atrial septal defect 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

NKX2-5: BP4, BP7, BS1 -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

This alteration is classified as likely 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

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.080

DANN

Benign

0.54

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