rs2472737

Positions:

• chr10-43120057-G-A
• chr10-43120057-G-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.2608-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,611,680 control chromosomes in the GnomAD database, including 39,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3284 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35940 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.305

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=-0.8).
• BP6: Variant 10-43120057-G-A is Benign according to our data. Variant chr10-43120057-G-A is described in ClinVar as [Benign]. Clinvar id is 24956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43120057-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.2608-24G>A		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2608-24G>A		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30780 AN: 152050 Hom.: 3272 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.204 AC: 50418 AN: 247006 Hom.: 5325 AF XY: 0.204 AC XY: 27337 AN XY: 133778

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.233

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.219 AC: 319375 AN: 1459512 Hom.: 35940 Cov.: 37 AF XY: 0.217 AC XY: 157520 AN XY: 725856

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.203 AC: 30818 AN: 152168 Hom.: 3284 Cov.: 33 AF XY: 0.206 AC XY: 15282 AN XY: 74364

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.198

Alfa AF: 0.197 Hom.: 1108

Bravo AF: 0.193

Asia WGS AF: 0.187 AC: 653 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16118333, 21222160) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Multiple endocrine neoplasia type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Multiple endocrine neoplasia, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.74

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: rs2472737; hg19: chr10-43615505; COSMIC: COSV60686346;