6-24174793-T-A

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.1368A>T(p.Lys456Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,613,154 control chromosomes in the GnomAD database, including 8,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (4079 hom., cov: 32)
  • Exomes 𝑓: 0.039 (4497 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16

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=0.0032149553).
• BP6: Variant 6-24174793-T-A is Benign according to our data. Variant chr6-24174793-T-A is described in ClinVar as [Benign]. Clinvar id is 508595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCDC2	NM_016356.5	c.1368A>T	p.Lys456Asn	missense_variant	10/10	ENST00000378454.8
DCDC2	NM_001195610.2	c.1368A>T	p.Lys456Asn	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCDC2	ENST00000378454.8	c.1368A>T	p.Lys456Asn	missense_variant	10/10	1	NM_016356.5	P1
DCDC2	ENST00000378450.6	c.627A>T	p.Lys209Asn	missense_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21702 AN: 152000 Hom.: 4078 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0832

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0500 AC: 12552 AN: 251094 Hom.: 1666 AF XY: 0.0404 AC XY: 5481 AN XY: 135732

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0389 AC: 56887 AN: 1461036 Hom.: 4497 Cov.: 32 AF XY: 0.0363 AC XY: 26369 AN XY: 726854

Gnomad4 AFR exome AF: 0.459

Gnomad4 AMR exome AF: 0.0514

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0513

GnomAD4 genome AF: 0.143 AC: 21731 AN: 152118 Hom.: 4079 Cov.: 32 AF XY: 0.137 AC XY: 10208 AN XY: 74388

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.124

Alfa AF: 0.0427 Hom.: 471

Bravo AF: 0.163

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.418 AC: 1840

ESP6500EA AF: 0.0286 AC: 246

ExAC AF: 0.0559 AC: 6790

Asia WGS AF: 0.0280 AC: 99 AN: 3476

EpiCase AF: 0.0254

EpiControl AF: 0.0257

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 25, 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

May 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.049
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.087
Sift	Benign	0.030	D;T
Sift4G	Benign	0.15	T;T
Polyphen		0.93	P;P
Vest4		0.067
MutPred		0.094		.;Loss of ubiquitination at K456 (P = 0.0022);
MPC		0.25
ClinPred		0.016	T
GERP RS		3.3
Varity_R		0.084
gMVP		0.17

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: rs9460973; hg19: chr6-24175021; COSMIC: COSV65828677;