11-30952568-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001387274.1(DCDC1):c.2592G>T(p.Arg864Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,273,900 control chromosomes in the GnomAD database, including 7,884 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (954 hom., cov: 32)
  • Exomes 𝑓: 0.10 (6930 hom.)
• Consequence: DCDC1 NM_001387274.1 missense, splice_region
• Scores: Splicing: ADA: 0.1448
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0250

Genes affected

DCDC1 (HGNC:20625): (doublecortin domain containing 1) This gene encodes a member of the doublecortin family. The protein encoded by this gene is a hydrophilic, intracellular protein. It contains a single doublecortin domain and is unable to bind microtubules and to regulate microtubule polymerization. This gene is mainly expressed in adult testis. It does not have a mouse homolog. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017987788).
• BP6: Variant 11-30952568-C-A is Benign according to our data. Variant chr11-30952568-C-A is described in ClinVar as [Benign]. Clinvar id is 3060329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCDC1	NM_001387274.1	c.2592G>T	p.Arg864Ser	missense_variant, splice_region_variant	21/39	ENST00000684477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCDC1	ENST00000684477.1	c.2592G>T	p.Arg864Ser	missense_variant, splice_region_variant	21/39		NM_001387274.1	A2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15319 AN: 151834 Hom.: 954 Cov.: 32

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0982

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.132 AC: 25049 AN: 189408 Hom.: 2042 AF XY: 0.128 AC XY: 13227 AN XY: 103146

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.160

Gnomad SAS exome AF: 0.120

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0993

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.103 AC: 115266 AN: 1121952 Hom.: 6930 Cov.: 14 AF XY: 0.103 AC XY: 58458 AN XY: 566366

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0925

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.101 AC: 15323 AN: 151948 Hom.: 954 Cov.: 32 AF XY: 0.105 AC XY: 7787 AN XY: 74244

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0983

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0979 Hom.: 1124

Bravo AF: 0.108

TwinsUK AF: 0.0903 AC: 335

ALSPAC AF: 0.0911 AC: 351

ESP6500AA AF: 0.0487 AC: 177

ESP6500EA AF: 0.104 AC: 850

ExAC AF: 0.114 AC: 13492

Asia WGS AF: 0.167 AC: 578 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DCDC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as 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	Pathogenic	0.89
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.66
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0018	T
MutationTaster	Benign	1.1e-14	P;P
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.057	T
Vest4		0.70
GERP RS		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs158633; hg19: chr11-30974115; COSMIC: COSV60304670;