rs33914824

chr6-24301818-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016356.5(DCDC2):c.454C>G(p.Pro152Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0391 in 1,614,066 control chromosomes in the GnomAD database, including 1,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P152P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (124 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1227 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.59

Genes affected

DCDC2 (HGNC:18141): (doublecortin domain containing 2) This gene encodes a doublecortin domain-containing family member. The doublecortin domain has been demonstrated to bind tubulin and enhance microtubule polymerization. This family member is thought to function in neuronal migration where it may affect the signaling of primary cilia. Mutations in this gene have been associated with reading disability (RD) type 2, also referred to as developmental dyslexia. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004606217).
• BP6: Variant 6-24301818-G-C is Benign according to our data. Variant chr6-24301818-G-C is described in ClinVar as [Benign]. Clinvar id is 466326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCDC2	NM_016356.5	c.454C>G	p.Pro152Ala	missense_variant	4/10	ENST00000378454.8
DCDC2	NM_001195610.2	c.454C>G	p.Pro152Ala	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCDC2	ENST00000378454.8	c.454C>G	p.Pro152Ala	missense_variant	4/10	1	NM_016356.5	P1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5971 AN: 152108 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0387

GnomAD3 exomes AF: 0.0373 AC: 9377 AN: 251470 Hom.: 247 AF XY: 0.0384 AC XY: 5215 AN XY: 135908

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0570

Gnomad EAS exome AF: 0.0114

Gnomad SAS exome AF: 0.0539

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0419

Gnomad OTH exome AF: 0.0456

GnomAD4 exome AF: 0.0391 AC: 57199 AN: 1461840 Hom.: 1227 Cov.: 30 AF XY: 0.0397 AC XY: 28857 AN XY: 727216

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.0256

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.0168

Gnomad4 SAS exome AF: 0.0527

Gnomad4 FIN exome AF: 0.0177

Gnomad4 NFE exome AF: 0.0396

Gnomad4 OTH exome AF: 0.0428

GnomAD4 genome AF: 0.0393 AC: 5979 AN: 152226 Hom.: 124 Cov.: 32 AF XY: 0.0374 AC XY: 2786 AN XY: 74434

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.0519

Gnomad4 EAS AF: 0.0148

Gnomad4 SAS AF: 0.0631

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0424

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0428 Hom.: 98

Bravo AF: 0.0413

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0355 AC: 137

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.0420 AC: 361

ExAC AF: 0.0383 AC: 4652

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0473

EpiControl AF: 0.0465

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 66;C4479344:Isolated neonatal sclerosing cholangitis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0046	T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.44
Sift	Benign	0.037	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.44
ClinPred		0.019	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.41

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: rs33914824; hg19: chr6-24302046; COSMIC: COSV65831955;