rs761596254

Variant names:

• chr5-173232705-G-A
• rs761596254
• NM_004387.4:c.839C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004387.4(NKX2-5):​c.839C>T​(p.Pro280Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,609,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P280P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.43
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15902731).
• BP6: Variant 5-173232705-G-A is Benign according to our data. Variant chr5-173232705-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468246.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000788 (12/152262) while in subpopulation AMR AF = 0.000589 (9/15288). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	NM_004387.4	MANE Select	c.839C>T	p.Pro280Leu	missense	Exon 2 of 2	NP_004378.1	P52952-1
	NKX2-5	NM_001166176.2		c.*638C>T		3_prime_UTR	Exon 2 of 2	NP_001159648.1	P52952-2
	NKX2-5	NM_001166175.2		c.*792C>T		3_prime_UTR	Exon 2 of 2	NP_001159647.1	P52952-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	ENST00000329198.5	TSL:1 MANE Select	c.839C>T	p.Pro280Leu	missense	Exon 2 of 2	ENSP00000327758.4	P52952-1
	NKX2-5	ENST00000424406.2	TSL:1	c.*792C>T		downstream_gene	N/A	ENSP00000395378.2	P52952-3
	NKX2-5	ENST00000521848.1	TSL:2	c.*638C>T		downstream_gene	N/A	ENSP00000427906.1	P52952-2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000655 AC: 16 AN: 244416 AF XY: 0.0000823

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000640

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1457726 Hom.: 0 Cov.: 35 AF XY: 0.0000386 AC XY: 28 AN XY: 724598

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.000157 AC: 7 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52174

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1109800

Other (OTH) AF: 0.0000831 AC: 5 AN: 60178

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74388

African (AFR) AF: 0.00 AC: 0 AN: 41482

American (AMR) AF: 0.000589 AC: 9 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Atrial septal defect 7 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	NKX2-5-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.050	N
PhyloP100		4.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.19
Sift	Benign	0.032	D
Sift4G	Uncertain	0.023	D
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.24		Loss of glycosylation at P280 (P = 0.0126)
MVP		0.71
MPC		0.51
ClinPred		0.057	T
GERP RS		3.4
Varity_R		0.069
gMVP		0.62
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs761596254; hg19: chr5-172659708;