8-133238971-C-CGAGCGGCTGCGGGTGCCCTCGCTGGTGTGGGAGCGGCTTCGGGTGCCCTCGCTGGTGTGG

Position:

• chr8-133238971-C-CGAGCGGCTGCGGGTGCCCTCGCTGGTGTGGGAGCGGCTTCGGGTGCCCTCGCTGGTGTGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_006096.4(NDRG1):​c.1091_1092insCCACACCAGCGAGGGCACCCGAAGCCGCTCCCACACCAGCGAGGGCACCCGCAGCCGCTC​(p.Thr350_Gly369dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0000066 in 151,586 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S364S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDRG1 NM_006096.4 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a modified_residue Phosphoserine; by SGK1 (size 0) in uniprot entity NDRG1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006096.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDRG1	NM_006096.4	c.1091_1092insCCACACCAGCGAGGGCACCCGAAGCCGCTCCCACACCAGCGAGGGCACCCGCAGCCGCTC	p.Thr350_Gly369dup	inframe_insertion	16/16	ENST00000323851.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDRG1	ENST00000323851.13	c.1091_1092insCCACACCAGCGAGGGCACCCGAAGCCGCTCCCACACCAGCGAGGGCACCCGCAGCCGCTC	p.Thr350_Gly369dup	inframe_insertion	16/16	1	NM_006096.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151586 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.97e-7 AC: 1 AN: 1435572 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 711474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74022

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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: 0.00

ClinVar

Not reported in ClinVar

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: rs1554747479; hg19: chr8-134251214;