rs2277923

Positions:

• chr5-173235021-T-A
• chr5-173235021-T-C
• chr5-173235021-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_004387.4(NKX2-5):​c.63A>T​(p.Glu21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E21Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-5 NM_004387.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.607

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-173235023-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.63A>T	p.Glu21Asp	missense_variant	1/2	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.63A>T	p.Glu21Asp	missense_variant	1/2		NP_001159648.1
NKX2-5	NM_001166175.2	c.63A>T	p.Glu21Asp	missense_variant	1/2		NP_001159647.1
NKX2-5	XM_017009071.3	c.63A>T	p.Glu21Asp	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.63A>T	p.Glu21Asp	missense_variant	1/2	1	NM_004387.4	ENSP00000327758	P1
NKX2-5	ENST00000424406.2	c.63A>T	p.Glu21Asp	missense_variant	1/2	1		ENSP00000395378
NKX2-5	ENST00000521848.1	c.63A>T	p.Glu21Asp	missense_variant	1/2	2		ENSP00000427906
NKX2-5	ENST00000517440.1	c.63A>T	p.Glu21Asp	missense_variant	1/2	4		ENSP00000429905

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;T
Eigen	Benign	0.036
Eigen_PC	Benign	-0.0019
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.1	M;M;M;.
MutationTaster	Benign	0.00013	P;P;P
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		0.46	P;.;.;D
Vest4		0.42
MutPred		0.26		Loss of phosphorylation at S26 (P = 0.2097);Loss of phosphorylation at S26 (P = 0.2097);Loss of phosphorylation at S26 (P = 0.2097);Loss of phosphorylation at S26 (P = 0.2097);
MVP		0.77
MPC		1.2
ClinPred		0.92	D
GERP RS		2.9
Varity_R		0.20
gMVP		0.73

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: rs2277923; hg19: chr5-172662024;