chr6-24290975-T-C

Variant names:

• chr6-24290975-T-C
• rs2274305
• NM_016356.5:c.661A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_016356.5(DCDC2):​c.661A>G​(p.Ser221Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,613,216 control chromosomes in the GnomAD database, including 344,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S221N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.52 (25455 hom., cov: 32)
  • Exomes 𝑓: 0.65 (318979 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.35
• Publications: 53 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 6-24290975-T-C is Benign according to our data. Variant chr6-24290975-T-C is described in ClinVar as Benign. ClinVar VariationId is 516888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 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.661A>G	p.Ser221Gly	missense	Exon 5 of 10	NP_057440.2	Q9UHG0-1
	DCDC2	NM_001195610.2		c.661A>G	p.Ser221Gly	missense	Exon 6 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.661A>G	p.Ser221Gly	missense	Exon 5 of 10	ENSP00000367715.3	Q9UHG0-1
	DCDC2	ENST00000883243.1		c.661A>G	p.Ser221Gly	missense	Exon 6 of 11	ENSP00000553302.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79752 AN: 151970 Hom.: 25451 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.746

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.654 AC: 164087 AN: 251070 AF XY: 0.660

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.745

Gnomad ASJ exome AF: 0.679

Gnomad EAS exome AF: 0.801

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.656

GnomAD4 exome AF: 0.654 AC: 955781 AN: 1461128 Hom.: 318979 Cov.: 43 AF XY: 0.656 AC XY: 476950 AN XY: 726906

African (AFR) AF: 0.117 AC: 3916 AN: 33470

American (AMR) AF: 0.732 AC: 32696 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 17650 AN: 26124

East Asian (EAS) AF: 0.785 AC: 31146 AN: 39662

South Asian (SAS) AF: 0.661 AC: 57005 AN: 86178

European-Finnish (FIN) AF: 0.743 AC: 39657 AN: 53386

Middle Eastern (MID) AF: 0.592 AC: 3411 AN: 5762

European-Non Finnish (NFE) AF: 0.659 AC: 732166 AN: 1111492

Other (OTH) AF: 0.632 AC: 38134 AN: 60366

GnomAD4 genome AF: 0.524 AC: 79758 AN: 152088 Hom.: 25455 Cov.: 32 AF XY: 0.535 AC XY: 39747 AN XY: 74344

African (AFR) AF: 0.140 AC: 5806 AN: 41496

American (AMR) AF: 0.638 AC: 9754 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2400 AN: 3470

East Asian (EAS) AF: 0.792 AC: 4095 AN: 5172

South Asian (SAS) AF: 0.658 AC: 3175 AN: 4822

European-Finnish (FIN) AF: 0.746 AC: 7887 AN: 10572

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44732 AN: 67962

Other (OTH) AF: 0.541 AC: 1141 AN: 2108

Alfa AF: 0.617 Hom.: 148623

Bravo AF: 0.496

TwinsUK AF: 0.662 AC: 2454

ALSPAC AF: 0.664 AC: 2559

ESP6500AA AF: 0.154 AC: 678

ESP6500EA AF: 0.651 AC: 5597

ExAC AF: 0.639 AC: 77563

Asia WGS AF: 0.682 AC: 2375 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.651

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive nonsyndromic hearing loss 66 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 66;C4479344:Isolated neonatal sclerosing cholangitis (1)
-	-	1	Isolated neonatal sclerosing cholangitis (1)
-	-	1	Nephronophthisis 19 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.65	N
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.23
Sift	Benign	0.22	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.099
ClinPred		0.0045	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.22
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: 0

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

Other links and lift over

dbSNP: rs2274305; hg19: chr6-24291203; COSMIC: COSV65834136;