rs794729665

chr6-24178385-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_016356.5(DCDC2):c.1271A>C(p.Gln424Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q424Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DCDC2 NM_016356.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.716

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-24178385-T-G is Pathogenic according to our data. Variant chr6-24178385-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 161160.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-24178385-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.31371993).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCDC2	NM_016356.5	c.1271A>C	p.Gln424Pro	missense_variant	9/10	ENST00000378454.8
DCDC2	NM_001195610.2	c.1271A>C	p.Gln424Pro	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCDC2	ENST00000378454.8	c.1271A>C	p.Gln424Pro	missense_variant	9/10	1	NM_016356.5	P1
DCDC2	ENST00000378450.6	c.530A>C	p.Gln177Pro	missense_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Nonsyndromic Deafness Pathogenic:1

Pathogenic, no assertion criteria provided

research

Centre de Biotechnologie de Sfax, Université de Sfax

Oct 01, 2014

- -

Autosomal recessive nonsyndromic hearing loss 66 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	11
Dann	Uncertain	0.98
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.99	D;P
Vest4		0.76
MutPred		0.14		.;Gain of loop (P = 0.0166);
MVP		0.72
MPC		0.13
ClinPred		0.30	T
GERP RS		4.1
Varity_R		0.37
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs794729665; hg19: chr6-24178613;