rs9467075

Positions:

• chr6-24205008-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016356.5(DCDC2):​c.1017C>T​(p.Val339Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,612,470 control chromosomes in the GnomAD database, including 15,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1454 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14066 hom.)
• Consequence: DCDC2 NM_016356.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.29

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-24205008-G-A is Benign according to our data. Variant chr6-24205008-G-A is described in ClinVar as [Benign]. Clinvar id is 517825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCDC2	NM_016356.5	c.1017C>T	p.Val339Val	synonymous_variant	8/10	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2	c.1017C>T	p.Val339Val	synonymous_variant	9/11		NP_001182539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8	c.1017C>T	p.Val339Val	synonymous_variant	8/10	1	NM_016356.5	ENSP00000367715.3
DCDC2	ENST00000378450.6	c.276C>T	p.Val92Val	synonymous_variant	1/3	1		ENSP00000367711.3

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20492 AN: 151952 Hom.: 1452 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0473

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.125 AC: 31389 AN: 250326 Hom.: 2180 AF XY: 0.129 AC XY: 17451 AN XY: 135214

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0893

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0509

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.0676

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.135 AC: 197766 AN: 1460400 Hom.: 14066 Cov.: 32 AF XY: 0.136 AC XY: 98972 AN XY: 726374

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0938

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.0444

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.0703

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.135 AC: 20506 AN: 152070 Hom.: 1454 Cov.: 32 AF XY: 0.130 AC XY: 9677 AN XY: 74318

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0648

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.159

Alfa AF: 0.148 Hom.: 1563

Bravo AF: 0.140

Asia WGS AF: 0.0970 AC: 336 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.156

ClinVar

Significance: Benign

Submissions summary: Benign:5

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. -

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.064
DANN	Benign	0.82

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: rs9467075; hg19: chr6-24205236; COSMIC: COSV65829034;