rs9460973

Variant names:

• chr6-24174793-T-A
• rs9460973
• NM_016356.5:c.1368A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016356.5(DCDC2):​c.1368A>T​(p.Lys456Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,613,154 control chromosomes in the GnomAD database, including 8,576 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (4079 hom., cov: 32)
  • Exomes 𝑓: 0.039 (4497 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.16
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• isolated neonatal sclerosing cholangitis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• nephronophthisis 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Boichis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 66

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032149553).
• BP6: Variant 6-24174793-T-A is Benign according to our data. Variant chr6-24174793-T-A is described in ClinVar as Benign. ClinVar VariationId is 508595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016356.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCDC2	NM_016356.5	MANE Select	c.1368A>T	p.Lys456Asn	missense	Exon 10 of 10	NP_057440.2	Q9UHG0-1
	DCDC2	NM_001195610.2		c.1368A>T	p.Lys456Asn	missense	Exon 11 of 11	NP_001182539.1	Q9UHG0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCDC2	ENST00000378454.8	TSL:1 MANE Select	c.1368A>T	p.Lys456Asn	missense	Exon 10 of 10	ENSP00000367715.3	Q9UHG0-1
	DCDC2	ENST00000378450.6	TSL:1	c.627A>T	p.Lys209Asn	missense	Exon 3 of 3	ENSP00000367711.3	Q9UHG0-2
	DCDC2	ENST00000883243.1		c.1368A>T	p.Lys456Asn	missense	Exon 11 of 11	ENSP00000553302.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21702 AN: 152000 Hom.: 4078 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0832

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.0500 AC: 12552 AN: 251094 AF XY: 0.0404

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0389 AC: 56887 AN: 1461036 Hom.: 4497 Cov.: 32 AF XY: 0.0363 AC XY: 26369 AN XY: 726854

African (AFR) AF: 0.459 AC: 15323 AN: 33382

American (AMR) AF: 0.0514 AC: 2296 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 717 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86200

European-Finnish (FIN) AF: 0.00399 AC: 213 AN: 53372

Middle Eastern (MID) AF: 0.0382 AC: 220 AN: 5766

European-Non Finnish (NFE) AF: 0.0313 AC: 34811 AN: 1111516

Other (OTH) AF: 0.0513 AC: 3095 AN: 60350

GnomAD4 genome AF: 0.143 AC: 21731 AN: 152118 Hom.: 4079 Cov.: 32 AF XY: 0.137 AC XY: 10208 AN XY: 74388

African (AFR) AF: 0.437 AC: 18106 AN: 41418

American (AMR) AF: 0.0830 AC: 1270 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1925 AN: 68008

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.0427 Hom.: 471

Bravo AF: 0.163

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.418 AC: 1840

ESP6500EA AF: 0.0286 AC: 246

ExAC AF: 0.0559 AC: 6790

Asia WGS AF: 0.0280 AC: 99 AN: 3476

EpiCase AF: 0.0254

EpiControl AF: 0.0257

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive nonsyndromic hearing loss 66;C4479344:Isolated neonatal sclerosing cholangitis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.049
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.087
Sift	Benign	0.030	D
Sift4G	Benign	0.15	T
Polyphen		0.93	P
Vest4		0.067
MutPred		0.094		Loss of ubiquitination at K456 (P = 0.0022)
MPC		0.25
ClinPred		0.016	T
GERP RS		3.3
Varity_R		0.084
gMVP		0.17
Mutation Taster		=65/35	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9460973; hg19: chr6-24175021; COSMIC: COSV65828677;