8-133238956-CCCCTCGCTGGTGTGCGAGCGGCTGCGGGTG-CCCCTCGCTGGTGTGCGAGCGGCTGCGGGTGCCCTCGCTGGTGTGCGAGCGGCTGCGGGTG

Position:

• chr8-133238956-CCCCTCGCTGGTGTGCGAGCGGCTGCGGGTG-CCCCTCGCTGGTGTGCGAGCGGCTGCGGGTGCCCTCGCTGGTGTGCGAGCGGCTGCGGGTG

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_006096.4(NDRG1):​c.1106_1107insCACCCGCAGCCGCTCGCACACCAGCGAGGG​(p.Thr360_Gly369dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 151,974 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G369G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDRG1 NM_006096.4 inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006096.4.
• BP6: Variant 8-133238956-C-CCCCTCGCTGGTGTGCGAGCGGCTGCGGGTG is Benign according to our data. Variant chr8-133238956-C-CCCCTCGCTGGTGTGCGAGCGGCTGCGGGTG is described in ClinVar as [Likely_benign]. Clinvar id is 476843.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 = 0.00116 (176/151974) while in subpopulation AFR AF= 0.00399 (165/41358). AF 95% confidence interval is 0.00349. There are 2 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4	c.1106_1107insCACCCGCAGCCGCTCGCACACCAGCGAGGG	p.Thr360_Gly369dup	inframe_insertion	16/16	ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13	c.1106_1107insCACCCGCAGCCGCTCGCACACCAGCGAGGG	p.Thr360_Gly369dup	inframe_insertion	16/16	1	NM_006096.4	P1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 151856 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000122 AC: 23 AN: 188768 Hom.: 0 AF XY: 0.000167 AC XY: 17 AN XY: 101502

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000897 AC: 128 AN: 1426454 Hom.: 0 Cov.: 30 AF XY: 0.0000991 AC XY: 70 AN XY: 706078

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000913

Gnomad4 OTH exome AF: 0.000339

GnomAD4 genome AF: 0.00116 AC: 176 AN: 151974 Hom.: 2 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74286

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2021

In-frame duplication of 10 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Charcot-Marie-Tooth disease type 4D Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 29, 2021

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554747463; hg19: chr8-134251199;