rs794727131

Variant names:

• chr10-43119592-G-A
• rs794727131
• NM_020975.6:c.2454G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43119592-G-A
• chr10-43119592-G-C
• chr10-43119592-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_020975.6(RET):​c.2454G>A​(p.Glu818Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.0370
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 10-43119592-G-A is Benign according to our data. Variant chr10-43119592-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194426.
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.

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.2454G>A	p.Glu818Glu	synonymous	Exon 14 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2454G>A	p.Glu818Glu	synonymous	Exon 14 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2454G>A	p.Glu818Glu	synonymous	Exon 14 of 20	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2454G>A	p.Glu818Glu	synonymous	Exon 14 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2454G>A	p.Glu818Glu	synonymous	Exon 14 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2190G>A	p.Glu730Glu	synonymous	Exon 14 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459880 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726324

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Multiple endocrine neoplasia type 2A (1)
-	1	-	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)
-	-	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	-0.52
CADD	Benign	1.4
DANN	Benign	0.30
PhyloP100		0.037
Mutation Taster		=100/0	polymorphism

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: rs794727131; hg19: chr10-43615040; COSMIC: COSV60705037; COSMIC: COSV60705037;