6-24357542-G-T

Position:

• chr6-24357542-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016356.5(DCDC2):​c.209C>A​(p.Thr70Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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]

KAAG1 (HGNC:21031): (kidney associated DCDC2 antisense RNA 1)

KAAG1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18191865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCDC2	NM_016356.5	c.209C>A	p.Thr70Asn	missense_variant	1/10	ENST00000378454.8	NP_057440.2
DCDC2	NM_001195610.2	c.209C>A	p.Thr70Asn	missense_variant	2/11		NP_001182539.1
KAAG1	NR_174942.1	n.640G>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCDC2	ENST00000378454.8	c.209C>A	p.Thr70Asn	missense_variant	1/10	1	NM_016356.5	ENSP00000367715.3
KAAG1	ENST00000274766.2	n.640G>T		non_coding_transcript_exon_variant	1/1	6	NM_181337.4
DCDC2	ENST00000436313.1	c.110C>A	p.Thr37Asn	missense_variant	1/3	3		ENSP00000410939.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461192 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.209C>A (p.T70N) alteration is located in exon 1 (coding exon 1) of the DCDC2 gene. This alteration results from a C to A substitution at nucleotide position 209, causing the threonine (T) at amino acid position 70 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.20
Sift	Benign	0.40	T
Sift4G	Benign	0.38	T
Polyphen		0.010	B
Vest4		0.13
MutPred		0.48		Loss of catalytic residue at T70 (P = 0.0445);
MVP		0.86
MPC		1.1
ClinPred		0.081	T
GERP RS		3.8
Varity_R		0.036
gMVP		0.39

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: rs1178039571; hg19: chr6-24357770;