5-173232508-C-G

Variant names:

• chr5-173232508-C-G
• rs703752
• NM_004387.4:c.*61G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004387.4(NKX2-5):​c.*61G>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 0.000034 in 1,589,640 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: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.816
• Publications: 31 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
• hypothyroidism, congenital, nongoitrous, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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)
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS2: High AC in GnomAd4 at 10 AD,Unknown,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.*61G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*835G>C		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*989G>C		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.*61G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_004387.4	ENSP00000327758.4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000306 AC: 44 AN: 1437374 Hom.: 0 Cov.: 42 AF XY: 0.0000280 AC XY: 20 AN XY: 714614

African (AFR) AF: 0.000240 AC: 8 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 42794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39366

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1107064

Other (OTH) AF: 0.0000334 AC: 2 AN: 59910

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74434

African (AFR) AF: 0.000241 AC: 10 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 28563

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.61
PhyloP100		-0.82

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: rs703752; hg19: chr5-172659511;