NM_001347721.2:c.-76-24325C>G

Variant names:

• chr21-37395974-C-G
• rs2251085
• NM_001347721.2:c.-76-24325C>G

Variant summary

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

The NM_001347721.2(DYRK1A):​c.-76-24325C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 151,994 control chromosomes in the GnomAD database, including 23,258 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 0.55 (23258 hom., cov: 31)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974
• Publications: 1 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347721.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.-76-24325C>G		intron	N/A	NP_001334650.1
	DYRK1A	NM_001396.5		c.-76-24325C>G		intron	N/A	NP_001387.2
	DYRK1A	NM_001347722.2		c.-76-24325C>G		intron	N/A	NP_001334651.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.-76-24325C>G		intron	N/A	ENSP00000494572.1
	DYRK1A	ENST00000398960.7	TSL:1	c.-77+20857C>G		intron	N/A	ENSP00000381932.2
	DYRK1A	ENST00000338785.8	TSL:1	c.-177-14596C>G		intron	N/A	ENSP00000342690.3

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83020 AN: 151876 Hom.: 23220 Cov.: 31

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.568

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

GnomAD4 genome AF: 0.547 AC: 83116 AN: 151994 Hom.: 23258 Cov.: 31 AF XY: 0.543 AC XY: 40333 AN XY: 74290

African (AFR) AF: 0.671 AC: 27787 AN: 41426

American (AMR) AF: 0.467 AC: 7137 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1932 AN: 3468

East Asian (EAS) AF: 0.432 AC: 2233 AN: 5166

South Asian (SAS) AF: 0.528 AC: 2543 AN: 4814

European-Finnish (FIN) AF: 0.510 AC: 5386 AN: 10556

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.506 AC: 34369 AN: 67954

Other (OTH) AF: 0.571 AC: 1206 AN: 2112

Alfa AF: 0.530 Hom.: 2620

Bravo AF: 0.548

Asia WGS AF: 0.512 AC: 1780 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	10
DANN	Benign	0.62
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2251085; hg19: chr21-38768276;