NM_016356.5:c.769C>A

Variant names:

• chr6-24278202-G-T
• rs909339162
• NM_016356.5:c.769C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016356.5(DCDC2):​c.769C>A​(p.Arg257Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,262 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.79
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.769C>A	p.Arg257Ser	missense	Exon 7 of 10	NP_057440.2	Q9UHG0-1
	DCDC2	NM_001195610.2		c.769C>A	p.Arg257Ser	missense	Exon 8 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.769C>A	p.Arg257Ser	missense	Exon 7 of 10	ENSP00000367715.3	Q9UHG0-1
	DCDC2	ENST00000883243.1		c.769C>A	p.Arg257Ser	missense	Exon 8 of 11	ENSP00000553302.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454262 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723140

African (AFR) AF: 0.00 AC: 0 AN: 32820

American (AMR) AF: 0.00 AC: 0 AN: 42948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 83998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109860

Other (OTH) AF: 0.00 AC: 0 AN: 60056

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0075	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.10	T
Sift4G	Uncertain	0.028	D
Polyphen		0.98	D
Vest4		0.48
MutPred		0.34		Gain of phosphorylation at R257 (P = 0.0045)
MVP		0.64
MPC		0.48
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.35
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs909339162; hg19: chr6-24278430; COSMIC: COSV65834283;