8-23702462-T-G

Variant names:

• chr8-23702462-T-G
• rs564297816
• NM_001136271.3:c.895A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001136271.3(NKX2-6):​c.895A>C​(p.Arg299Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,325,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: NKX2-6 NM_001136271.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.

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.895A>C	p.Arg299Arg	synonymous	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.895A>C	p.Arg299Arg	synonymous	Exon 2 of 2	ENSP00000320089.3	A6NCS4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.54e-7 AC: 1 AN: 1325958 Hom.: 0 Cov.: 32 AF XY: 0.00000155 AC XY: 1 AN XY: 645776

African (AFR) AF: 0.00 AC: 0 AN: 30142

American (AMR) AF: 0.00 AC: 0 AN: 29184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21104

East Asian (EAS) AF: 0.00 AC: 0 AN: 34888

South Asian (SAS) AF: 0.00 AC: 0 AN: 69544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5294

European-Non Finnish (NFE) AF: 9.57e-7 AC: 1 AN: 1044746

Other (OTH) AF: 0.00 AC: 0 AN: 55098

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.9
DANN	Benign	0.78
PhyloP100		-1.3

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

dbSNP: rs564297816; hg19: chr8-23559975;