6-24290975-T-C

Position:

chr6-24290975-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000378454.8(DCDC2):c.661A>G(p.Ser221Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,613,216 control chromosomes in the GnomAD database, including 344,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S221N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.52 ( 25455 hom., cov: 32)

Exomes 𝑓: 0.65 ( 318979 hom. )

Consequence

DCDC2
ENST00000378454.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.35

Variant links:

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]

DCDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 6-24290975-T-C is Benign according to our data. Variant chr6-24290975-T-C is described in ClinVar as [Benign]. Clinvar id is 516888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24290975-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCDC2	NM_016356.5 linkuse as main transcript	c.661A>G	p.Ser221Gly	missense_variant	5/10	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2 linkuse as main transcript	c.661A>G	p.Ser221Gly	missense_variant	6/11		NP_001182539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8 linkuse as main transcript	c.661A>G	p.Ser221Gly	missense_variant	5/10	1	NM_016356.5	ENSP00000367715	P1	Q9UHG0-1

Frequencies

GnomAD3 genomes

AF:

0.525

AC:

79752

AN:

151970

Hom.:

25451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.669

Gnomad AMR

AF:

0.638

Gnomad ASJ

AF:

0.692

Gnomad EAS

AF:

0.791

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.746

Gnomad MID

AF:

0.560

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.539

GnomAD3 exomes

AF:

0.654

AC:

164087

AN:

251070

Hom.:

56707

AF XY:

0.660

AC XY:

89646

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.745

Gnomad ASJ exome

AF:

0.679

Gnomad EAS exome

AF:

0.801

Gnomad SAS exome

AF:

0.660

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.656

GnomAD4 exome

AF:

0.654

AC:

955781

AN:

1461128

Hom.:

318979

Cov.:

AF XY:

0.656

AC XY:

476950

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.117

Gnomad4 AMR exome

AF:

0.732

Gnomad4 ASJ exome

AF:

0.676

Gnomad4 EAS exome

AF:

0.785

Gnomad4 SAS exome

AF:

0.661

Gnomad4 FIN exome

AF:

0.743

Gnomad4 NFE exome

AF:

0.659

Gnomad4 OTH exome

AF:

0.632

GnomAD4 genome

AF:

0.524

AC:

79758

AN:

152088

Hom.:

25455

Cov.:

AF XY:

0.535

AC XY:

39747

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.638

Gnomad4 ASJ

AF:

0.692

Gnomad4 EAS

AF:

0.792

Gnomad4 SAS

AF:

0.658

Gnomad4 FIN

AF:

0.746

Gnomad4 NFE

AF:

0.658

Gnomad4 OTH

AF:

0.541

Alfa

AF:

0.635

Hom.:

80062

Bravo

AF:

0.496

TwinsUK

AF:

0.662

AC:

2454

ALSPAC

AF:

0.664

AC:

2559

ESP6500AA

AF:

0.154

AC:

678

ESP6500EA

AF:

0.651

AC:

5597

ExAC

AF:

0.639

AC:

77563

Asia WGS

AF:

0.682

AC:

2375

AN:

3478

EpiCase

AF:

0.645

EpiControl

AF:

0.651

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 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. -

Isolated neonatal sclerosing cholangitis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autosomal recessive nonsyndromic hearing loss 66

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Nephronophthisis 19

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.035

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.65

MutationTaster

Benign

0.15

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.19

REVEL

Benign

0.23

Sift

Benign

0.22

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.031

MPC

0.099

ClinPred

0.0045

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.64

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over