rs2272651

Variant names:

• chr8-133258305-T-C
• rs2272651
• NM_006096.4:c.450+61A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-133258305-T-C
• chr8-133258305-T-A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.187
• Publications: 10 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: Benign. The variant received -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 VariationId 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.

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.450+61A>G		intron	N/A	NP_006087.2
	NDRG1	NM_001374844.1		c.450+61A>G		intron	N/A	NP_001361773.1
	NDRG1	NM_001135242.2		c.450+61A>G		intron	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.450+61A>G		intron	N/A	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000522476.5	TSL:1	c.252+61A>G		intron	N/A	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000414097.6	TSL:2	c.450+61A>G		intron	N/A	ENSP00000404854.2	Q92597-1

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

African (AFR) AF: 0.361 AC: 11370 AN: 31488

American (AMR) AF: 0.298 AC: 11109 AN: 37232

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8198 AN: 25052

East Asian (EAS) AF: 0.0752 AC: 2829 AN: 37612

South Asian (SAS) AF: 0.271 AC: 21534 AN: 79566

European-Finnish (FIN) AF: 0.223 AC: 11192 AN: 50080

Middle Eastern (MID) AF: 0.355 AC: 2001 AN: 5638

European-Non Finnish (NFE) AF: 0.278 AC: 289891 AN: 1044442

Other (OTH) AF: 0.273 AC: 15601 AN: 57108

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

African (AFR) AF: 0.352 AC: 14611 AN: 41452

American (AMR) AF: 0.313 AC: 4785 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1118 AN: 3472

East Asian (EAS) AF: 0.0596 AC: 309 AN: 5188

South Asian (SAS) AF: 0.263 AC: 1265 AN: 4810

European-Finnish (FIN) AF: 0.217 AC: 2300 AN: 10582

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19293 AN: 67970

Other (OTH) AF: 0.301 AC: 636 AN: 2112

Alfa AF: 0.288 Hom.: 24058

Bravo AF: 0.304

Asia WGS AF: 0.188 AC: 657 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		0.19
PromoterAI		0.017	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs2272651;

hg19: chr8-134270548;