rs1032793565

Positions:

• chr5-173234878-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_004387.4(NKX2-5):​c.206T>G​(p.Leu69Arg) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L69P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3345586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.206T>G	p.Leu69Arg	missense_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.206T>G	p.Leu69Arg	missense_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2	c.206T>G	p.Leu69Arg	missense_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3	c.206T>G	p.Leu69Arg	missense_variant	1/2		XP_016864560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000329198.5	c.206T>G	p.Leu69Arg	missense_variant	1/2	1	NM_004387.4	ENSP00000327758	P1
NKX2-5	ENST00000424406.2	c.206T>G	p.Leu69Arg	missense_variant	1/2	1		ENSP00000395378
NKX2-5	ENST00000521848.1	c.206T>G	p.Leu69Arg	missense_variant	1/2	2		ENSP00000427906
NKX2-5	ENST00000517440.1	c.206T>G	p.Leu69Arg	missense_variant	1/2	4		ENSP00000429905

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NKX2-5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 69 of the NKX2-5 protein (p.Leu69Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;.;T
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.010	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.10	T;D;D;D
Sift4G	Benign	0.64	T;T;T;.
Polyphen		0.88	P;.;.;B
Vest4		0.55
MutPred		0.25		Loss of stability (P = 0.0232);Loss of stability (P = 0.0232);Loss of stability (P = 0.0232);Loss of stability (P = 0.0232);
MVP		0.86
MPC		1.7
ClinPred		0.78	D
GERP RS		3.9
Varity_R		0.20
gMVP		0.59

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: rs1032793565; hg19: chr5-172661881;