rs2154545

Variant names:

• chr21-37498982-G-A
• rs2154545
• NM_001347721.2:c.1212+2724G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-37498982-G-A
• chr21-37498982-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001347721.2(DYRK1A):​c.1212+2724G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 151,638 control chromosomes in the GnomAD database, including 14,379 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14379 hom., cov: 31)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.950
• Publications: 3 publications found

Genes affected

DYRK1A (HGNC:3091): (dual specificity tyrosine phosphorylation regulated kinase 1A) This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. This gene is a homolog of Drosophila mnb (minibrain) gene and rat Dyrk gene. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Alternative splicing of this gene generates several transcript variants differing from each other either in the 5' UTR or in the 3' coding region. These variants encode at least five different isoforms. [provided by RefSeq, Jul 2008]

DYRK1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• DYRK1A-related intellectual disability syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYRK1A	NM_001347721.2	c.1212+2724G>A		intron_variant	Intron 9 of 11	ENST00000647188.2	NP_001334650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYRK1A	ENST00000647188.2	c.1212+2724G>A		intron_variant	Intron 9 of 11		NM_001347721.2	ENSP00000494572.1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63760 AN: 151518 Hom.: 14342 Cov.: 31

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.429

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.421 AC: 63850 AN: 151638 Hom.: 14379 Cov.: 31 AF XY: 0.420 AC XY: 31124 AN XY: 74086

African (AFR) AF: 0.582 AC: 24061 AN: 41312

American (AMR) AF: 0.353 AC: 5382 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1200 AN: 3460

East Asian (EAS) AF: 0.429 AC: 2208 AN: 5150

South Asian (SAS) AF: 0.431 AC: 2072 AN: 4808

European-Finnish (FIN) AF: 0.375 AC: 3927 AN: 10466

Middle Eastern (MID) AF: 0.399 AC: 114 AN: 286

European-Non Finnish (NFE) AF: 0.349 AC: 23701 AN: 67882

Other (OTH) AF: 0.434 AC: 913 AN: 2106

Alfa AF: 0.370 Hom.: 8646

Bravo AF: 0.429

Asia WGS AF: 0.458 AC: 1596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.65
DANN	Benign	0.34
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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: rs2154545; hg19: chr21-38871285;