chr8-23702713-C-G

Variant names:

• chr8-23702713-C-G
• NM_001136271.3:c.644G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001136271.3(NKX2-6):​c.644G>C​(p.Arg215Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R215H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX2-6 NM_001136271.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• Publications: 0 publications found

Genes affected

NKX2-6 (HGNC:32940): (NK2 homeobox 6) This gene encodes a homeobox-containing protein that belongs to the NK-2 homeobox family. This protein is a vertebrate homolog of Drosophila homeobox-containing protein called 'tinman', which has been shown to be essential for development of the heart-like dorsal vessel. In conjunction with related gene, NKX2-5, this gene may play a role in both pharyngeal and cardiac embryonic development. Mutations in this gene are associated with persistent truncus arteriosus.[provided by RefSeq, Aug 2011]

NKX2-6 Gene-Disease associations (from GenCC):

• conotruncal heart malformations

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LOC107986930 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136271.3. 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
	NKX2-6	NM_001136271.3	MANE Select	c.644G>C	p.Arg215Pro	missense	Exon 2 of 2	NP_001129743.2	A6NCS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX2-6	ENST00000325017.4	TSL:2 MANE Select	c.644G>C	p.Arg215Pro	missense	Exon 2 of 2	ENSP00000320089.3	A6NCS4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.39		Loss of solvent accessibility (P = 0.0703)
MVP		0.42
MPC		1.6
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.53
gMVP		0.85
Mutation Taster		=75/25	polymorphism

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

hg19: chr8-23560226;