rs28936670

Positions:

• chr5-173235011-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004387.4(NKX2-5):​c.73C>T​(p.Arg25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,236 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0099 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (30 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 B:8
• Conservation: PhyloP100: 0.972

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007823437).
• BP6: Variant 5-173235011-G-A is Benign according to our data. Variant chr5-173235011-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9008.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}. Variant chr5-173235011-G-A is described in Lovd as [Benign]. Variant chr5-173235011-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00992 (1511/152326) while in subpopulation AFR AF= 0.0319 (1325/41582). AF 95% confidence interval is 0.0304. There are 23 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.73C>T	p.Arg25Cys	missense_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.73C>T	p.Arg25Cys	missense_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2	c.73C>T	p.Arg25Cys	missense_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3	c.73C>T	p.Arg25Cys	missense_variant	1/2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.73C>T	p.Arg25Cys	missense_variant	1/2	1	NM_004387.4	ENSP00000327758	P1
NKX2-5	ENST00000424406.2	c.73C>T	p.Arg25Cys	missense_variant	1/2	1		ENSP00000395378
NKX2-5	ENST00000521848.1	c.73C>T	p.Arg25Cys	missense_variant	1/2	2		ENSP00000427906
NKX2-5	ENST00000517440.1	c.73C>T	p.Arg25Cys	missense_variant	1/2	4		ENSP00000429905

Frequencies

GnomAD3 genomes AF: 0.00991 AC: 1509 AN: 152208 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00343 AC: 832 AN: 242556 Hom.: 12 AF XY: 0.00296 AC XY: 393 AN XY: 132950

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00618

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00201 AC: 2929 AN: 1459910 Hom.: 30 Cov.: 31 AF XY: 0.00193 AC XY: 1401 AN XY: 726278

Gnomad4 AFR exome AF: 0.0340

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00552

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00992 AC: 1511 AN: 152326 Hom.: 23 Cov.: 33 AF XY: 0.00891 AC XY: 664 AN XY: 74488

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00291 Hom.: 3

Bravo AF: 0.0114

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0265 AC: 115

ESP6500EA AF: 0.000937 AC: 8

ExAC AF: 0.00371 AC: 448

Asia WGS AF: 0.00347 AC: 12 AN: 3474

EpiCase AF: 0.00169

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2012	Arg25Cys in exon 1 of NKX2-5: This variant has been reported in a large number o f individuals with congenital heart disease (Akcaboy 2008, Benson 1999, DeLuca 2 010, Esposito 2009, Goli-Pereira 2010, Goldmuntz 2001, McElhinny 2003, Raunch 20 10, Stallmeyer 2010). This variant is now considered to be benign based on its h igh population frequency (2.6%) in the Black population (97/3694 chromosomes, NH LBI Exome Variant Project http://evs.gs.washington.edu/EVS/). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2015	- -

Atrial septal defect 7 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hypoplastic left heart syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Truncus arteriosus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Aortic arch interruption Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Hypothyroidism, congenital, nongoitrous, 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Tetralogy of Fallot Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

NKX2-5: BS1, BS2 -

Congenital heart disease Benign:1

Benign, no assertion criteria provided

clinical testing

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

Jun 04, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2015

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	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.39	T;T;T;T
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	0.95	A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N;D;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.040	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;.
Polyphen		0.0020	B;.;.;B
Vest4		0.24
MVP		0.87
MPC		1.6
ClinPred		0.026	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.42

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

Other links and lift over

dbSNP: rs28936670; hg19: chr5-172662014; COSMIC: COSV61298694;