21-37512066-TCACCACCACCACCAC-TCACCACCACCACCACCACCAC

Variant names:

• chr21-37512066-T-TCACCAC
• rs760576043
• NM_001347721.2:c.1812_1817dupCCACCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6_Very_Strong BS2_Supporting

The NM_001347721.2(DYRK1A):​c.1812_1817dupCCACCA​(p.His605_His606dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000899 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H606H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: DYRK1A NM_001347721.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.79
• 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001347721.2
• BP6: Variant 21-37512066-T-TCACCAC is Benign according to our data. Variant chr21-37512066-T-TCACCAC is described in ClinVar as Likely_benign. ClinVar VariationId is 429953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 14 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1812_1817dupCCACCA	p.His605_His606dup	disruptive_inframe_insertion	Exon 12 of 12	NP_001334650.1
	DYRK1A	NM_001396.5		c.1839_1844dupCCACCA	p.His614_His615dup	disruptive_inframe_insertion	Exon 12 of 12	NP_001387.2
	DYRK1A	NM_001347722.2		c.1812_1817dupCCACCA	p.His605_His606dup	disruptive_inframe_insertion	Exon 12 of 12	NP_001334651.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.1812_1817dupCCACCA	p.His605_His606dup	disruptive_inframe_insertion	Exon 12 of 12	ENSP00000494572.1
	DYRK1A	ENST00000398960.7	TSL:1	c.1839_1844dupCCACCA	p.His614_His615dup	disruptive_inframe_insertion	Exon 12 of 12	ENSP00000381932.2
	DYRK1A	ENST00000338785.8	TSL:1	c.*215_*220dupCCACCA		3_prime_UTR	Exon 13 of 13	ENSP00000342690.3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000799 AC: 20 AN: 250312 AF XY: 0.0000813

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461758 Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65 AN XY: 727176

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111940

Other (OTH) AF: 0.0000662 AC: 4 AN: 60392

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74216

African (AFR) AF: 0.0000967 AC: 4 AN: 41346

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67978

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	DYRK1A-related intellectual disability syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=67/33	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs760576043; hg19: chr21-38884369;