rs2255526

Variant names:

• chr21-46551626-G-A
• rs2255526
• NM_015151.4:c.2840-8G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_015151.4(DIP2A):​c.2840-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,611,488 control chromosomes in the GnomAD database, including 414,457 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.75 (42857 hom., cov: 33)
  • Exomes 𝑓: 0.71 (371600 hom.)
• Consequence: DIP2A NM_015151.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006456
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.478
• Publications: 17 publications found

Genes affected

DIP2A (HGNC:17217): (disco interacting protein 2 homolog A) The protein encoded by this gene may be involved in axon patterning in the central nervous system. This gene is not highly expressed. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

DIP2A Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-46551626-G-A is Benign according to our data. Variant chr21-46551626-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060466.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIP2A	NM_015151.4	c.2840-8G>A		splice_region_variant, intron_variant	Intron 23 of 37	ENST00000417564.3	NP_055966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIP2A	ENST00000417564.3	c.2840-8G>A		splice_region_variant, intron_variant	Intron 23 of 37	1	NM_015151.4	ENSP00000392066.2
DIP2A	ENST00000651436.1	c.2840-8G>A		splice_region_variant, intron_variant	Intron 23 of 38			ENSP00000498874.1
DIP2A	ENST00000400274.5	c.2828-8G>A		splice_region_variant, intron_variant	Intron 23 of 37	5		ENSP00000383133.1
DIP2A	ENST00000850580.1	n.2840-8G>A		splice_region_variant, intron_variant	Intron 23 of 38			ENSP00000520868.1

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113408 AN: 152028 Hom.: 42811 Cov.: 33

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.731

GnomAD2 exomes AF: 0.708 AC: 174843 AN: 246932 AF XY: 0.704

Gnomad AFR exome AF: 0.876

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.639

Gnomad EAS exome AF: 0.757

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.716

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.713 AC: 1039939 AN: 1459342 Hom.: 371600 Cov.: 35 AF XY: 0.710 AC XY: 515254 AN XY: 725772

African (AFR) AF: 0.876 AC: 29297 AN: 33448

American (AMR) AF: 0.657 AC: 29231 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 16561 AN: 26104

East Asian (EAS) AF: 0.728 AC: 28871 AN: 39656

South Asian (SAS) AF: 0.682 AC: 58712 AN: 86086

European-Finnish (FIN) AF: 0.666 AC: 35517 AN: 53340

Middle Eastern (MID) AF: 0.675 AC: 3890 AN: 5762

European-Non Finnish (NFE) AF: 0.716 AC: 794852 AN: 1110158

Other (OTH) AF: 0.713 AC: 43008 AN: 60300

GnomAD4 genome AF: 0.746 AC: 113510 AN: 152146 Hom.: 42857 Cov.: 33 AF XY: 0.738 AC XY: 54846 AN XY: 74366

African (AFR) AF: 0.870 AC: 36106 AN: 41512

American (AMR) AF: 0.669 AC: 10230 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2149 AN: 3472

East Asian (EAS) AF: 0.742 AC: 3845 AN: 5180

South Asian (SAS) AF: 0.675 AC: 3262 AN: 4830

European-Finnish (FIN) AF: 0.647 AC: 6828 AN: 10556

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48749 AN: 68002

Other (OTH) AF: 0.732 AC: 1540 AN: 2104

Alfa AF: 0.728 Hom.: 28271

Bravo AF: 0.756

Asia WGS AF: 0.738 AC: 2569 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DIP2A-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.018
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: rs2255526; hg19: chr21-47971539;