rs377225752

Variant names:

• chr8-133250475-G-A
• rs377225752
• NM_006096.4:c.663C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-133250475-G-A
• chr8-133250475-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_006096.4(NDRG1):​c.663C>T​(p.Pro221Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P221P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: NDRG1 NM_006096.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.951
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-133250475-G-A is Benign according to our data. Variant chr8-133250475-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362036.
• BP7: Synonymous conserved (PhyloP=-0.951 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	NM_006096.4	MANE Select	c.663C>T	p.Pro221Pro	synonymous	Exon 10 of 16	NP_006087.2
	NDRG1	NM_001374844.1		c.714C>T	p.Pro238Pro	synonymous	Exon 10 of 16	NP_001361773.1
	NDRG1	NM_001135242.2		c.663C>T	p.Pro221Pro	synonymous	Exon 10 of 16	NP_001128714.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.663C>T	p.Pro221Pro	synonymous	Exon 10 of 16	ENSP00000319977.8
	NDRG1	ENST00000522476.5	TSL:1	c.465C>T	p.Pro155Pro	synonymous	Exon 8 of 14	ENSP00000427894.1
	NDRG1	ENST00000414097.6	TSL:2	c.663C>T	p.Pro221Pro	synonymous	Exon 10 of 16	ENSP00000404854.2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152032 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000219 AC: 55 AN: 251492 AF XY: 0.000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000935 AC XY: 68 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111996

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152032 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74254

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Charcot-Marie-Tooth disease type 4 (2)
-	1	-	Charcot-Marie-Tooth disease type 4D (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.44
PhyloP100		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs377225752; hg19: chr8-134262718;