21-34521506-C-T

Variant names:

• chr21-34521506-C-T
• rs1984545323
• NM_004414.7:c.579G>A
• RCAN1 p.Leu193Leu

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004414.7(RCAN1):​c.579G>A​(p.Leu193Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: RCAN1 NM_004414.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.10
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=-3.1 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004414.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCAN1	NM_004414.7	MANE Select	c.579G>A	p.Leu193Leu	synonymous	Exon 3 of 4	NP_004405.3
	RCAN1	NM_001285391.2		c.654G>A	p.Leu218Leu	synonymous	Exon 3 of 4	NP_001272320.2	E9PDJ2
	RCAN1	NM_001331016.2		c.414G>A	p.Leu138Leu	synonymous	Exon 3 of 3	NP_001317945.1	V9GYW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCAN1	ENST00000313806.9	TSL:1 MANE Select	c.579G>A	p.Leu193Leu	synonymous	Exon 3 of 4	ENSP00000320768.4	P53805-1
	RCAN1	ENST00000381132.6	TSL:1	c.414G>A	p.Leu138Leu	synonymous	Exon 3 of 4	ENSP00000370524.2	P53805-2
	RCAN1	ENST00000399272.5	TSL:1	c.336G>A	p.Leu112Leu	synonymous	Exon 3 of 4	ENSP00000382214.1	P53805-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.6
DANN	Benign	0.76
PhyloP100		-3.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1984545323;

hg19: chr21-35893804;