Genetic Variant NM_001099434.2:c.126G>C (chr1-32209219-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001099434.2(DCDC2B):c.126G>C(p.Glu42Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E42K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DCDC2B
NM_001099434.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.581

Variant links:

Genes affected

DCDC2B (HGNC:32576): (doublecortin domain containing 2B) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains. The doublecortin domain has been demonstrated to bind tubulin and enhance microtubule polymerization. [provided by RefSeq, Sep 2010]

DCDC2B links:

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ACMG classification

Classification made for transcript

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=0.30102694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCDC2B	NM_001099434.2 link	c.126G>C	p.Glu42Asp	missense_variant	Exon 1 of 9	ENST00000409358.2	NP_001092904.1	A2VCK2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCDC2B	ENST00000409358.2 link	c.126G>C	p.Glu42Asp	missense_variant	Exon 1 of 9	1	NM_001099434.2	ENSP00000386870.1		A2VCK2
DCDC2B	ENST00000487056.1 link	n.124G>C		non_coding_transcript_exon_variant	Exon 1 of 7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.126G>C (p.E42D) alteration is located in exon 1 (coding exon 1) of the DCDC2B gene. This alteration results from a G to C substitution at nucleotide position 126, causing the glutamic acid (E) at amino acid position 42 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

0.32

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.71

M_CAP

Benign

0.039

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.34

Sift

Benign

0.14

Sift4G

Benign

0.079

Polyphen

0.54

Vest4

0.33

MutPred

0.54

Loss of helix (P = 0.1299);

MVP

0.74

MPC

0.13

ClinPred

0.77

GERP RS

0.91

Varity_R

0.14

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over