rs2506004

Positions:

• chr10-43086825-A-C
• chr10-43086825-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020975.6(RET):​c.73+9494A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 152,216 control chromosomes in the GnomAD database, including 46,962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.78 (46962 hom., cov: 35)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0130

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-43086825-A-C is Benign according to our data. Variant chr10-43086825-A-C is described in ClinVar as [Benign]. Clinvar id is 695195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.73+9494A>C		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.73+9494A>C		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118338 AN: 152098 Hom.: 46897 Cov.: 35

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.778 AC: 118468 AN: 152216 Hom.: 46962 Cov.: 35 AF XY: 0.771 AC XY: 57345 AN XY: 74416

Gnomad4 AFR AF: 0.916

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.542

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.747

Gnomad4 OTH AF: 0.771

Alfa AF: 0.679 Hom.: 2959

Bravo AF: 0.795

Asia WGS AF: 0.648 AC: 2256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2019

This variant is associated with the following publications: (PMID: 20977903) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.77

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: rs2506004; hg19: chr10-43582273; COSMIC: COSV60690807;