8-133239097-GCG-CAA

Variant names:

• chr8-133239097-GCG-CAA
• NM_006096.4:c.964_966delCGCinsTTG
• NDRG1 p.Arg322Leu

Variant summary

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

The NM_006096.4(NDRG1):​c.964_966delCGCinsTTG​(p.Arg322Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDRG1 NM_006096.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• Publications: 0 publications found

Genes affected

NDRG1 (HGNC:7679): (N-myc downstream regulated 1) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation. The encoded protein is necessary for p53-mediated caspase activation and apoptosis. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4D, and expression of this gene may be a prognostic indicator for several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

NDRG1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006096.4. 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
	NDRG1	NM_006096.4	MANE Select	c.964_966delCGCinsTTG	p.Arg322Leu	missense	N/A	NP_006087.2
	NDRG1	NM_001374844.1		c.1015_1017delCGCinsTTG	p.Arg339Leu	missense	N/A	NP_001361773.1
	NDRG1	NM_001135242.2		c.964_966delCGCinsTTG	p.Arg322Leu	missense	N/A	NP_001128714.1	Q92597-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.964_966delCGCinsTTG	p.Arg322Leu	missense	N/A	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000522476.5	TSL:1	c.766_768delCGCinsTTG	p.Arg256Leu	missense	N/A	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000414097.6	TSL:2	c.964_966delCGCinsTTG	p.Arg322Leu	missense	N/A	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-134251340;