6-24174738-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_016356.5(DCDC2):c.1423G>A(p.Val475Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,611,036 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.803

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018259704).
• BP6: Variant 6-24174738-C-T is Benign according to our data. Variant chr6-24174738-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 593401.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000565 (86/152232) while in subpopulation AFR AF= 0.00154 (64/41532). AF 95% confidence interval is 0.00124. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCDC2	NM_016356.5	c.1423G>A	p.Val475Met	missense_variant	10/10	ENST00000378454.8
DCDC2	NM_001195610.2	c.1423G>A	p.Val475Met	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCDC2	ENST00000378454.8	c.1423G>A	p.Val475Met	missense_variant	10/10	1	NM_016356.5	P1
DCDC2	ENST00000378450.6	c.682G>A	p.Val228Met	missense_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 251130 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135736

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000823 AC: 120 AN: 1458804 Hom.: 0 Cov.: 31 AF XY: 0.0000799 AC XY: 58 AN XY: 725918

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000960

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74438

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000326 Hom.: 0

Bravo AF: 0.000544

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	DCDC2: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2022	BP4 -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 475 of the DCDC2 protein (p.Val475Met). This variant is present in population databases (rs145154884, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DCDC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 593401). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

DCDC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.64	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;P
Vest4		0.21
MVP		0.69
MPC		0.41
ClinPred		0.025	T
GERP RS		3.9
Varity_R		0.066
gMVP		0.21

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: rs145154884; hg19: chr6-24174966; COSMIC: COSV65829299;