3-129171743-C-G

Position:

• chr3-129171743-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003418.5(CNBP):​c.15G>C​(p.Glu5Asp) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CNBP NM_003418.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.913

Genes affected

CNBP (HGNC:13164): (CCHC-type zinc finger nucleic acid binding protein) This gene encodes a nucleic-acid binding protein with seven zinc-finger domains. The protein has a preference for binding single stranded DNA and RNA. The protein functions in cap-independent translation of ornithine decarboxylase mRNA, and may also function in sterol-mediated transcriptional regulation. A CCTG expansion from <30 repeats to 75-11000 repeats in the first intron of this gene results in myotonic dystrophy type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNBP
• BP4: Computational evidence support a benign effect (MetaRNN=0.25697437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNBP	NM_003418.5	c.15G>C	p.Glu5Asp	missense_variant	2/5	ENST00000422453.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNBP	ENST00000422453.7	c.15G>C	p.Glu5Asp	missense_variant	2/5	1	NM_003418.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.15G>C (p.E5D) alteration is located in exon 2 (coding exon 1) of the CNBP gene. This alteration results from a G to C substitution at nucleotide position 15, causing the glutamic acid (E) at amino acid position 5 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	0.21
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;T;T;D;D;D;T;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.15	T;T;T;T;T;T;T;D
Sift4G	Benign	0.43	T;T;T;T;T;T;T;.
Polyphen		0.013	B;B;.;.;.;.;.;.
Vest4		0.25
MutPred		0.40		Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);Gain of glycosylation at S2 (P = 0.0266);
MVP		0.64
MPC		1.2
ClinPred		0.22	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.73

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: rs1937572819; hg19: chr3-128890586;