6-24174446-A-G

Variant names:

• chr6-24174446-A-G
• rs16888768
• NM_016356.5:c.*284T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016356.5(DCDC2):​c.*284T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 191,432 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (5 hom.)
• Consequence: DCDC2 NM_016356.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0500
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet
• nephronophthisis 19

  Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-24174446-A-G is Benign according to our data. Variant chr6-24174446-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250200.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0162 (2076/128292) while in subpopulation AFR AF = 0.0514 (1380/26874). AF 95% confidence interval is 0.0491. There are 28 homozygotes in GnomAd4. There are 947 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,Unknown gene

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.*284T>C		3_prime_UTR	Exon 10 of 10	NP_057440.2	Q9UHG0-1
	DCDC2	NM_001195610.2		c.*284T>C		3_prime_UTR	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.*284T>C		3_prime_UTR	Exon 10 of 10	ENSP00000367715.3	Q9UHG0-1
	DCDC2	ENST00000378450.6	TSL:1	c.*284T>C		3_prime_UTR	Exon 3 of 3	ENSP00000367711.3	Q9UHG0-2
	DCDC2	ENST00000883243.1		c.*284T>C		3_prime_UTR	Exon 11 of 11	ENSP00000553302.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2076 AN: 128198 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.000312

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000300

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00668

Gnomad OTH AF: 0.0174

GnomAD4 exome AF: 0.00656 AC: 414 AN: 63140 Hom.: 5 Cov.: 0 AF XY: 0.00633 AC XY: 211 AN XY: 33330

African (AFR) AF: 0.0371 AC: 68 AN: 1832

American (AMR) AF: 0.0120 AC: 34 AN: 2838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2508

East Asian (EAS) AF: 0.00 AC: 0 AN: 4056

South Asian (SAS) AF: 0.00 AC: 0 AN: 2352

European-Finnish (FIN) AF: 0.000363 AC: 1 AN: 2754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00655 AC: 277 AN: 42280

Other (OTH) AF: 0.00806 AC: 34 AN: 4218

GnomAD4 genome AF: 0.0162 AC: 2076 AN: 128292 Hom.: 28 Cov.: 33 AF XY: 0.0152 AC XY: 947 AN XY: 62472

African (AFR) AF: 0.0514 AC: 1380 AN: 26874

American (AMR) AF: 0.0173 AC: 231 AN: 13382

Ashkenazi Jewish (ASJ) AF: 0.000312 AC: 1 AN: 3202

East Asian (EAS) AF: 0.00 AC: 0 AN: 3198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4188

European-Finnish (FIN) AF: 0.000300 AC: 3 AN: 10016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00666 AC: 429 AN: 64404

Other (OTH) AF: 0.0172 AC: 32 AN: 1856

Alfa AF: 0.0109 Hom.: 1

Bravo AF: 0.0160

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.8
DANN	Benign	0.72
PhyloP100		-0.050
Mutation Taster		=100/0	polymorphism

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: rs16888768; hg19: chr6-24174674;