rs767243751

Positions:

• chr5-173234784-G-C
• chr5-173234784-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004387.4(NKX2-5):​c.300C>G​(p.Pro100=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P100P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-5 NM_004387.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.323

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 5-173234784-G-C is Benign according to our data. Variant chr5-173234784-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2971019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.323 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX2-5	NM_004387.4	c.300C>G	p.Pro100=	synonymous_variant	1/2	ENST00000329198.5
NKX2-5	NM_001166176.2	c.300C>G	p.Pro100=	synonymous_variant	1/2
NKX2-5	NM_001166175.2	c.300C>G	p.Pro100=	synonymous_variant	1/2
NKX2-5	XM_017009071.3	c.300C>G	p.Pro100=	synonymous_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX2-5	ENST00000329198.5	c.300C>G	p.Pro100=	synonymous_variant	1/2	1	NM_004387.4	P1
NKX2-5	ENST00000424406.2	c.300C>G	p.Pro100=	synonymous_variant	1/2	1
NKX2-5	ENST00000521848.1	c.300C>G	p.Pro100=	synonymous_variant	1/2	2
NKX2-5	ENST00000517440.1	c.300C>G	p.Pro100=	synonymous_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.7
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs767243751; hg19: chr5-172661787;