chr5-173234835-C-T

Variant names:

• chr5-173234835-C-T
• rs1442654880
• NM_004387.4:c.249G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_004387.4(NKX2-5):​c.249G>A​(p.Ala83Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A83A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NKX2-5 NM_004387.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.369
• Publications: 0 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-173234835-C-T is Benign according to our data. Variant chr5-173234835-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3698842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.369 with no splicing effect.

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.249G>A	p.Ala83Ala	synonymous	Exon 1 of 2	NP_004378.1
	NKX2-5	NM_001166176.2		c.249G>A	p.Ala83Ala	synonymous	Exon 1 of 2	NP_001159648.1
	NKX2-5	NM_001166175.2		c.249G>A	p.Ala83Ala	synonymous	Exon 1 of 2	NP_001159647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-5	ENST00000329198.5	TSL:1 MANE Select	c.249G>A	p.Ala83Ala	synonymous	Exon 1 of 2	ENSP00000327758.4
	NKX2-5	ENST00000424406.2	TSL:1	c.249G>A	p.Ala83Ala	synonymous	Exon 1 of 2	ENSP00000395378.2
	NKX2-5	ENST00000521848.1	TSL:2	c.249G>A	p.Ala83Ala	synonymous	Exon 1 of 2	ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000459 AC: 1 AN: 218050 AF XY: 0.00000835

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434604 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712100

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31274

American (AMR) AF: 0.00 AC: 0 AN: 40170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24426

East Asian (EAS) AF: 0.00 AC: 0 AN: 38624

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101076

Other (OTH) AF: 0.00 AC: 0 AN: 59038

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atrial septal defect 7 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.4
DANN	Benign	0.90
PhyloP100		-0.37
PromoterAI		-0.077	Neutral

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: rs1442654880; hg19: chr5-172661838;