chr21-34592787-T-C

Variant names:

• chr21-34592787-T-C
• rs9305551
• NM_004414.7:c.252+21973A>G

Variant summary

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

The NM_004414.7(RCAN1):​c.252+21973A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,236 control chromosomes in the GnomAD database, including 2,729 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 0.17 (2729 hom., cov: 32)
• Consequence: RCAN1 NM_004414.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506
• Publications: 6 publications found

Genes affected

RCAN1 (HGNC:3040): (regulator of calcineurin 1) The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways, possibly affecting central nervous system development. This gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of this gene may lead to neurofibrillary tangles such as those associated with Alzheimer disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

ENSG00000288711 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCAN1	NM_004414.7	c.252+21973A>G		intron_variant	Intron 1 of 3	ENST00000313806.9	NP_004405.3
RCAN1	NM_001285389.2	c.9+21000A>G		intron_variant	Intron 1 of 3		NP_001272318.1
RCAN1	NM_203417.2	c.-154+21491A>G		intron_variant	Intron 1 of 3		NP_981962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCAN1	ENST00000313806.9	c.252+21973A>G		intron_variant	Intron 1 of 3	1	NM_004414.7	ENSP00000320768.4
ENSG00000288711	ENST00000684114.1	n.153+21973A>G		intron_variant	Intron 1 of 4			ENSP00000507841.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26160 AN: 152118 Hom.: 2727 Cov.: 32

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.172 AC: 26160 AN: 152236 Hom.: 2729 Cov.: 32 AF XY: 0.171 AC XY: 12710 AN XY: 74442

African (AFR) AF: 0.0734 AC: 3049 AN: 41558

American (AMR) AF: 0.169 AC: 2582 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1036 AN: 3472

East Asian (EAS) AF: 0.0471 AC: 244 AN: 5176

South Asian (SAS) AF: 0.249 AC: 1199 AN: 4820

European-Finnish (FIN) AF: 0.164 AC: 1741 AN: 10608

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15449 AN: 67990

Other (OTH) AF: 0.183 AC: 386 AN: 2104

Alfa AF: 0.210 Hom.: 3402

Bravo AF: 0.167

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.0
DANN	Benign	0.77
PhyloP100		0.51
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: rs9305551; hg19: chr21-35965084;