dbSNP rs2233346: NDRG1:c.892-5C>T (chr8-133242079-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006096.4(NDRG1):c.892-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,188 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 40 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 35 hom. )

Consequence

NDRG1
NM_006096.4 splice_region, intron

Scores

Splicing: ADA: 0.00001699

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.956

Publications

1 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Orphanet, Illumina

NDRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 8-133242079-G-A is Benign according to our data. Variant chr8-133242079-G-A is described in ClinVar as Benign. ClinVar VariationId is 362033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1829/152320) while in subpopulation AFR AF = 0.0403 (1673/41562). AF 95% confidence interval is 0.0386. There are 40 homozygotes in GnomAd4. There are 855 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDRG1	NM_006096.4	MANE Select	c.892-5C>T	splice_region intron	N/A	NP_006087.2
NDRG1	NM_001374844.1		c.943-5C>T	splice_region intron	N/A	NP_001361773.1
NDRG1	NM_001135242.2		c.892-5C>T	splice_region intron	N/A	NP_001128714.1	Q92597-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.892-5C>T	splice_region intron	N/A	ENSP00000319977.8	Q92597-1
NDRG1	ENST00000522476.5	TSL:1	c.694-5C>T	splice_region intron	N/A	ENSP00000427894.1	Q92597-2
NDRG1	ENST00000414097.6	TSL:2	c.892-5C>T	splice_region intron	N/A	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1821

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0402

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00338

AC:

851

AN:

251458

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00148

AC:

2166

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

950

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0419

AC:

1403

AN:

33478

American (AMR)

AF:

0.00201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00941

AC:

246

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000171

AC:

190

AN:

1111994

Other (OTH)

AF:

0.00339

AC:

205

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0120

AC:

1829

AN:

152320

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

855

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0403

AC:

1673

AN:

41562

American (AMR)

AF:

0.00451

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68034

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

180

269

359

449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00719

Hom.:

Bravo

AF:

0.0136

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease type 4D (2)

not provided (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.1

(source)

DANN

Benign

0.61

PhyloP100

0.96

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over