rs2506023

Positions:

• chr10-43092411-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020975.6(RET):​c.74-8048T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,160 control chromosomes in the GnomAD database, including 11,584 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 0.38 (11584 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.74-8048T>C		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.74-8048T>C		intron_variant		5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58495 AN: 152042 Hom.: 11564 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.393

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

GnomAD4 genome AF: 0.385 AC: 58554 AN: 152160 Hom.: 11584 Cov.: 33 AF XY: 0.388 AC XY: 28838 AN XY: 74376

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.429

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.413

Gnomad4 OTH AF: 0.397

Alfa AF: 0.392 Hom.: 2389

Bravo AF: 0.384

Asia WGS AF: 0.461 AC: 1606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.30
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs2506023; hg19: chr10-43587859;