rs374485384

Positions:

• chr6-24353632-AAAAC-A
• chr6-24353632-AAAAC-AAAACAAAC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000378454.8(DCDC2):​c.294-13_294-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,561,562 control chromosomes in the GnomAD database, including 376 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 32)
  • Exomes 𝑓: 0.018 (352 hom.)
• Consequence: DCDC2 ENST00000378454.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0670

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 -16 ACMG points.

• BP6: Variant 6-24353632-AAAAC-A is Benign according to our data. Variant chr6-24353632-AAAAC-A is described in ClinVar as [Benign]. Clinvar id is 466324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2402/152340) while in subpopulation NFE AF= 0.0216 (1468/68028). AF 95% confidence interval is 0.0207. There are 24 homozygotes in gnomad4. There are 1219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCDC2	NM_016356.5	c.294-13_294-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2	c.294-13_294-10del		splice_polypyrimidine_tract_variant, intron_variant			NP_001182539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8	c.294-13_294-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_016356.5	ENSP00000367715	P1
DCDC2	ENST00000436313.1	c.197-13_197-10del		splice_polypyrimidine_tract_variant, intron_variant		3		ENSP00000410939

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2402 AN: 152222 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0151 AC: 3457 AN: 229264 Hom.: 40 AF XY: 0.0153 AC XY: 1904 AN XY: 124560

Gnomad AFR exome AF: 0.00563

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.000711

Gnomad SAS exome AF: 0.00371

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0181 AC: 25483 AN: 1409222 Hom.: 352 AF XY: 0.0177 AC XY: 12403 AN XY: 702366

Gnomad4 AFR exome AF: 0.00450

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.00403

Gnomad4 EAS exome AF: 0.000612

Gnomad4 SAS exome AF: 0.00386

Gnomad4 FIN exome AF: 0.0346

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0158 AC: 2402 AN: 152340 Hom.: 24 Cov.: 32 AF XY: 0.0164 AC XY: 1219 AN XY: 74506

Gnomad4 AFR AF: 0.00570

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0177 Hom.: 7

Bravo AF: 0.0130

Asia WGS AF: 0.00348 AC: 12 AN: 3466

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

Jan 31, 2018

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs374485384; hg19: chr6-24353860;