chr2-231455594-C-G

Position:

• chr2-231455594-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005381.3(NCL):​c.1863G>C​(p.Glu621Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCL NM_005381.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0830

Genes affected

NCL (HGNC:7667): (nucleolin) Nucleolin (NCL), a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes. It is located mainly in dense fibrillar regions of the nucleolus. Human NCL gene consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20. [provided by RefSeq, Jul 2008]

NCL (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38649428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCL	NM_005381.3	c.1863G>C	p.Glu621Asp	missense_variant	13/14	ENST00000322723.9	NP_005372.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCL	ENST00000322723.9	c.1863G>C	p.Glu621Asp	missense_variant	13/14	2	NM_005381.3	ENSP00000318195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 05, 2023

The c.1863G>C (p.E621D) alteration is located in exon 13 (coding exon 13) of the NCL gene. This alteration results from a G to C substitution at nucleotide position 1863, causing the glutamic acid (E) at amino acid position 621 to be replaced by an aspartic acid (D). 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	Benign	0.20
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.45	N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.22	T;T
Sift4G	Benign	0.52	T;.
Polyphen		0.59	P;.
Vest4		0.19
MutPred		0.46		Gain of sheet (P = 0.1208);.;
MVP		0.90
MPC		1.3
ClinPred		0.33	T
GERP RS		-2.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.8
Varity_R		0.10
gMVP		0.79

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: rs143429155; hg19: chr2-232320305;