rs1800862

Variant names:

• chr10-43119646-C-T
• rs1800862
• NM_020975.6:c.2508C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-43119646-C-T
• chr10-43119646-C-A
• chr10-43119646-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020975.6(RET):​c.2508C>T​(p.Ser836Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,264 control chromosomes in the GnomAD database, including 2,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (150 hom., cov: 34)
  • Exomes 𝑓: 0.049 (2105 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 3.34
• Publications: 90 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 10-43119646-C-T is Benign according to our data. Variant chr10-43119646-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 24946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0807 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.2508C>T	p.Ser836Ser	synonymous	Exon 14 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2508C>T	p.Ser836Ser	synonymous	Exon 14 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2508C>T	p.Ser836Ser	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.2508C>T	p.Ser836Ser	synonymous	Exon 14 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2508C>T	p.Ser836Ser	synonymous	Exon 14 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2244C>T	p.Ser748Ser	synonymous	Exon 14 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5979 AN: 152210 Hom.: 150 Cov.: 34

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0319

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0450 AC: 11248 AN: 250230 AF XY: 0.0495

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.000872

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0497

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0491 AC: 71669 AN: 1460936 Hom.: 2105 Cov.: 34 AF XY: 0.0506 AC XY: 36796 AN XY: 726788

African (AFR) AF: 0.0246 AC: 825 AN: 33474

American (AMR) AF: 0.0250 AC: 1120 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0538 AC: 1406 AN: 26126

East Asian (EAS) AF: 0.00106 AC: 42 AN: 39696

South Asian (SAS) AF: 0.0949 AC: 8188 AN: 86254

European-Finnish (FIN) AF: 0.0366 AC: 1925 AN: 52582

Middle Eastern (MID) AF: 0.0733 AC: 422 AN: 5760

European-Non Finnish (NFE) AF: 0.0494 AC: 54911 AN: 1111950

Other (OTH) AF: 0.0469 AC: 2830 AN: 60378

GnomAD4 genome AF: 0.0393 AC: 5988 AN: 152328 Hom.: 150 Cov.: 34 AF XY: 0.0397 AC XY: 2960 AN XY: 74478

African (AFR) AF: 0.0244 AC: 1014 AN: 41582

American (AMR) AF: 0.0365 AC: 559 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.0875 AC: 423 AN: 4832

European-Finnish (FIN) AF: 0.0319 AC: 339 AN: 10632

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3242 AN: 68004

Other (OTH) AF: 0.0535 AC: 113 AN: 2114

Alfa AF: 0.0435 Hom.: 75

Bravo AF: 0.0381

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.0541

EpiControl AF: 0.0541

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Multiple endocrine neoplasia (2)
-	-	2	Multiple endocrine neoplasia, type 2 (2)
-	-	2	Pheochromocytoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia type 2A (1)
-	-	1	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C1833921:Familial medullary thyroid carcinoma (1)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		3.3
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: rs1800862; hg19: chr10-43615094; COSMIC: COSV60687774;