rs2272651

Positions:

• chr8-133258305-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006096.4(NDRG1):​c.450+61A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,520,300 control chromosomes in the GnomAD database, including 59,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6922 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52714 hom.)
• Consequence: NDRG1 NM_006096.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.187

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-133258305-T-C is Benign according to our data. Variant chr8-133258305-T-C is described in ClinVar as [Benign]. Clinvar id is 670539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4	c.450+61A>G		intron_variant		ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13	c.450+61A>G		intron_variant		1	NM_006096.4	P1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44785 AN: 151964 Hom.: 6908 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.304

GnomAD4 exome AF: 0.273 AC: 373725 AN: 1368218 Hom.: 52714 AF XY: 0.273 AC XY: 185015 AN XY: 678654

Gnomad4 AFR exome AF: 0.361

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.327

Gnomad4 EAS exome AF: 0.0752

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.295 AC: 44843 AN: 152082 Hom.: 6922 Cov.: 32 AF XY: 0.290 AC XY: 21588 AN XY: 74350

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.301

Alfa AF: 0.287 Hom.: 10660

Bravo AF: 0.304

Asia WGS AF: 0.188 AC: 657 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease type 4D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.75

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: rs2272651; hg19: chr8-134270548;