chr14-21022081-C-G

Position:

• chr14-21022081-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001320329.2(NDRG2):​c.325G>C​(p.Ala109Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDRG2 NM_001320329.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

Genes affected

NDRG2 (HGNC:14460): (NDRG family member 2) 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 that may play a role in neurite outgrowth. This gene may be involved in glioblastoma carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDRG2	NM_001320329.2	c.325G>C	p.Ala109Pro	missense_variant	5/16	ENST00000556147.6	NP_001307258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDRG2	ENST00000556147.6	c.325G>C	p.Ala109Pro	missense_variant	5/16	5	NM_001320329.2	ENSP00000451712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.325G>C (p.A109P) alteration is located in exon 6 (coding exon 4) of the NDRG2 gene. This alteration results from a G to C substitution at nucleotide position 325, causing the alanine (A) at amino acid position 109 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T;.;T;.;T;.;.;T;.;T;.;T;.;.;.;.;.;T;T;T;T;T;T;T;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;T;T;T;.;T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;.;.;.;.;.;D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.3	M;.;M;.;.;.;.;M;.;M;.;M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;D;.;.;.;.;D;.;.;.;D;.;.;.;.;D;.;.;D;.;D;.;.;D;D;.;D;D;.;D
Polyphen		0.98	D;.;D;.;.;.;.;D;.;D;.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.87
MutPred		0.74		Gain of catalytic residue at A109 (P = 0.0016);.;Gain of catalytic residue at A109 (P = 0.0016);.;.;.;.;Gain of catalytic residue at A109 (P = 0.0016);.;Gain of catalytic residue at A109 (P = 0.0016);.;Gain of catalytic residue at A109 (P = 0.0016);Gain of catalytic residue at A109 (P = 0.0016);.;.;.;.;.;.;.;.;Gain of catalytic residue at A109 (P = 0.0016);.;.;.;.;Gain of catalytic residue at A109 (P = 0.0016);Gain of catalytic residue at A109 (P = 0.0016);.;.;.;Gain of catalytic residue at A109 (P = 0.0016);.;.;.;.;.;.;.;Gain of catalytic residue at A109 (P = 0.0016);Gain of catalytic residue at A109 (P = 0.0016);.;.;.;Gain of catalytic residue at A109 (P = 0.0016);Gain of catalytic residue at A109 (P = 0.0016);.;Gain of catalytic residue at A109 (P = 0.0016);.;Gain of catalytic residue at A109 (P = 0.0016);
MVP		0.63
MPC		0.83
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs1437469417; hg19: chr14-21490240;