rs200039950

chr5-173233371-C-Gchr5-173233371-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000424406.2(NKX2-5):c.*126G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NKX2-5 ENST00000424406.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0570

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11092529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.335-162G>C		intron_variant		ENST00000329198.5
NKX2-5	NM_001166176.2	c.428G>C	p.Arg143Pro	missense_variant	2/2
NKX2-5	NM_001166175.2	c.*126G>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000424406.2	c.*126G>C		3_prime_UTR_variant	2/2	1
NKX2-5	ENST00000329198.5	c.335-162G>C		intron_variant		1	NM_004387.4	P1
NKX2-5	ENST00000521848.1	c.428G>C	p.Arg143Pro	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000717 AC: 1 AN: 139470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 74830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384804 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 683336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000191 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	3.2
Dann	Benign	0.72
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Vest4		0.34
MutPred		0.30		Gain of loop (P = 0.0045);
MVP		0.42
ClinPred		0.075	T
GERP RS		-2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200039950; hg19: chr5-172660374;