5-173234847-C-T

Position:

• chr5-173234847-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The ENST00000329198.5(NKX2-5):​c.237G>A​(p.Pro79Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000696 in 1,436,404 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. P79P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: NKX2-5 ENST00000329198.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.72

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-173234847-C-T is Benign according to our data. Variant chr5-173234847-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.72 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.237G>A	p.Pro79Pro	synonymous_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.237G>A	p.Pro79Pro	synonymous_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2	c.237G>A	p.Pro79Pro	synonymous_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3	c.237G>A	p.Pro79Pro	synonymous_variant	1/2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.237G>A	p.Pro79Pro	synonymous_variant	1/2	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000424406.2	c.237G>A	p.Pro79Pro	synonymous_variant	1/2	1		ENSP00000395378.2
NKX2-5	ENST00000521848.1	c.237G>A	p.Pro79Pro	synonymous_variant	1/2	2		ENSP00000427906.1
NKX2-5	ENST00000517440.1	c.237G>A	p.Pro79Pro	synonymous_variant	1/2	4		ENSP00000429905.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000696 AC: 10 AN: 1436404 Hom.: 0 Cov.: 31 AF XY: 0.00000982 AC XY: 7 AN XY: 713190

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000817

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial septal defect 7 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	- -
Likely benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.13
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72554029; hg19: chr5-172661850;