rs2506004

Variant names:

• chr10-43086825-A-C
• rs2506004
• NM_020975.6:c.73+9494A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 publications found

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]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. 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
	RET	NM_020975.6	MANE Select	c.73+9494A>C		intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.73+9494A>C		intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.73+9494A>C		intron	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.73+9494A>C		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.73+9494A>C		intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.73+9494A>C		intron	N/A	ENSP00000519223.1	A0AAQ5BH28

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

African (AFR) AF: 0.916 AC: 38087 AN: 41566

American (AMR) AF: 0.759 AC: 11614 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2427 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2800 AN: 5168

South Asian (SAS) AF: 0.711 AC: 3426 AN: 4820

European-Finnish (FIN) AF: 0.636 AC: 6742 AN: 10598

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50781 AN: 67982

Other (OTH) AF: 0.771 AC: 1629 AN: 2114

Alfa AF: 0.694 Hom.: 3281

Bravo AF: 0.795

Asia WGS AF: 0.648 AC: 2256 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple endocrine neoplasia, type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.77
PhyloP100		0.013
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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