rs2233319

Variant names:

• chr8-133264553-T-C
• rs2233319
• ENST00000522476.5:c.1A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_001258432.2(NDRG1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,166 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (13 hom.)
• Consequence: NDRG1 NM_001258432.2 start_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.24
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, Illumina

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 16 codons. Genomic position: 133262129. Lost 0.047 part of the original CDS.
• BP6: Variant 8-133264553-T-C is Benign according to our data. Variant chr8-133264553-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362040.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 = 0.00775 (1181/152356) while in subpopulation AFR AF = 0.0251 (1045/41576). AF 95% confidence interval is 0.0239. There are 13 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258432.2. 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.199A>G	p.Met67Val	missense	Exon 4 of 16	NP_006087.2
	NDRG1	NM_001258432.2		c.1A>G	p.Met1?	start_lost	Exon 2 of 14	NP_001245361.1	Q92597-2
	NDRG1	NM_001374847.1		c.1A>G	p.Met1?	start_lost	Exon 3 of 15	NP_001361776.1	Q92597-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDRG1	ENST00000522476.5	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 2 of 14	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000323851.13	TSL:1 MANE Select	c.199A>G	p.Met67Val	missense	Exon 4 of 16	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000518480.5	TSL:4	c.1A>G	p.Met1?	start_lost	Exon 3 of 7	ENSP00000428802.1	E5RG99

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1179 AN: 152238 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00239 AC: 601 AN: 251482 AF XY: 0.00184

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000993 AC: 1451 AN: 1461810 Hom.: 13 Cov.: 30 AF XY: 0.000919 AC XY: 668 AN XY: 727226

African (AFR) AF: 0.0259 AC: 867 AN: 33470

American (AMR) AF: 0.00157 AC: 70 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00934 AC: 244 AN: 26136

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

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

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.0000890 AC: 99 AN: 1111950

Other (OTH) AF: 0.00250 AC: 151 AN: 60394

GnomAD4 genome AF: 0.00775 AC: 1181 AN: 152356 Hom.: 13 Cov.: 33 AF XY: 0.00756 AC XY: 563 AN XY: 74504

African (AFR) AF: 0.0251 AC: 1045 AN: 41576

American (AMR) AF: 0.00399 AC: 61 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68038

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00241 Hom.: 7

Bravo AF: 0.00890

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.014	B
Vest4		0.43
MVP		0.19
MPC		0.38
ClinPred		0.080	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.60
Mutation Taster		=138/62	polymorphism

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: rs2233319; hg19: chr8-134276796;