chr8-133247931-G-A

Variant names:

• chr8-133247931-G-A
• rs2227262
• NM_006096.4:c.756-5C>T

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.756-5C>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 0.147 in 1,613,166 control chromosomes in the GnomAD database, including 18,280 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 0.12 (1243 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17037 hom.)
• Consequence: NDRG1 NM_006096.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005743
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.84
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-133247931-G-A is Benign according to our data. Variant chr8-133247931-G-A is described in ClinVar as Benign. ClinVar VariationId is 138434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 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.756-5C>T		splice_region intron	N/A	NP_006087.2
	NDRG1	NM_001374844.1		c.807-5C>T		splice_region intron	N/A	NP_001361773.1
	NDRG1	NM_001135242.2		c.756-5C>T		splice_region 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.756-5C>T		splice_region intron	N/A	ENSP00000319977.8	Q92597-1
	NDRG1	ENST00000522476.5	TSL:1	c.558-5C>T		splice_region intron	N/A	ENSP00000427894.1	Q92597-2
	NDRG1	ENST00000414097.6	TSL:2	c.756-5C>T		splice_region intron	N/A	ENSP00000404854.2	Q92597-1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17582 AN: 152100 Hom.: 1243 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.139 AC: 35045 AN: 251486 AF XY: 0.146

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.150 AC: 218866 AN: 1460948 Hom.: 17037 Cov.: 32 AF XY: 0.152 AC XY: 110541 AN XY: 726792

African (AFR) AF: 0.0242 AC: 810 AN: 33468

American (AMR) AF: 0.108 AC: 4840 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4469 AN: 26128

East Asian (EAS) AF: 0.132 AC: 5250 AN: 39696

South Asian (SAS) AF: 0.188 AC: 16252 AN: 86232

European-Finnish (FIN) AF: 0.147 AC: 7845 AN: 53408

Middle Eastern (MID) AF: 0.189 AC: 1066 AN: 5640

European-Non Finnish (NFE) AF: 0.153 AC: 169633 AN: 1111294

Other (OTH) AF: 0.144 AC: 8701 AN: 60362

GnomAD4 genome AF: 0.115 AC: 17565 AN: 152218 Hom.: 1243 Cov.: 33 AF XY: 0.116 AC XY: 8642 AN XY: 74408

African (AFR) AF: 0.0308 AC: 1281 AN: 41554

American (AMR) AF: 0.111 AC: 1705 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3470

East Asian (EAS) AF: 0.101 AC: 525 AN: 5178

South Asian (SAS) AF: 0.195 AC: 941 AN: 4822

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10592

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10543 AN: 67984

Other (OTH) AF: 0.117 AC: 246 AN: 2110

Alfa AF: 0.142 Hom.: 2493

Bravo AF: 0.106

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.151

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Charcot-Marie-Tooth disease type 4 (2)
-	-	2	Charcot-Marie-Tooth disease type 4D (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.6
DANN	Benign	0.71
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0020
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: rs2227262; hg19: chr8-134260174; COSMIC: COSV60484259; COSMIC: COSV60484259;