chr21-34592787-T-C

Position:

• chr21-34592787-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
RCAN1	NM_004414.7	c.252+21973A>G		intron_variant		ENST00000313806.9	NP_004405.3
RCAN1	NM_001285389.2	c.9+21000A>G		intron_variant			NP_001272318.1
RCAN1	NM_203417.2	c.-154+21491A>G		intron_variant			NP_981962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCAN1	ENST00000313806.9	c.252+21973A>G		intron_variant		1	NM_004414.7	ENSP00000320768

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

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.0471

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.183

Alfa AF: 0.216 Hom.: 2216

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9305551; hg19: chr21-35965084;