10-43120185-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_020975.6(RET):c.2712C>G(p.Ser904Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,612,614 control chromosomes in the GnomAD database, including 29,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S904S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 2538 hom., cov: 33)

Exomes 𝑓: 0.19 ( 27229 hom. )

Consequence

RET
NM_020975.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: -0.752

Publications

131 publications found

Variant links:

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

RET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 10-43120185-C-G is Benign according to our data. Variant chr10-43120185-C-G is described in ClinVar as Benign. ClinVar VariationId is 24964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RET	NM_020975.6	MANE Select	c.2712C>G	p.Ser904Ser	synonymous	Exon 15 of 20	NP_066124.1	P07949-1
RET	NM_001406743.1		c.2712C>G	p.Ser904Ser	synonymous	Exon 15 of 21	NP_001393672.1	P07949-1
RET	NM_001406744.1		c.2712C>G	p.Ser904Ser	synonymous	Exon 15 of 20	NP_001393673.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RET	ENST00000355710.8	TSL:5 MANE Select	c.2712C>G	p.Ser904Ser	synonymous	Exon 15 of 20	ENSP00000347942.3	P07949-1
RET	ENST00000340058.6	TSL:1	c.2712C>G	p.Ser904Ser	synonymous	Exon 15 of 19	ENSP00000344798.4	P07949-2
RET	ENST00000713926.1		c.2448C>G	p.Ser816Ser	synonymous	Exon 15 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26367

AN:

152066

Hom.:

2539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.211

AC:

52714

AN:

249546

AF XY:

0.209

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.187

AC:

273006

AN:

1460432

Hom.:

27229

Cov.:

AF XY:

0.189

AC XY:

137082

AN XY:

726482

show subpopulations

African (AFR)

AF:

0.107

AC:

3573

AN:

33446

American (AMR)

AF:

0.339

AC:

15124

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

5198

AN:

26132

East Asian (EAS)

AF:

0.0944

AC:

3748

AN:

39686

South Asian (SAS)

AF:

0.257

AC:

22168

AN:

86156

European-Finnish (FIN)

AF:

0.213

AC:

11367

AN:

53242

Middle Eastern (MID)

AF:

0.257

AC:

1296

AN:

5048

European-Non Finnish (NFE)

AF:

0.179

AC:

199546

AN:

1111810

Other (OTH)

AF:

0.182

AC:

10986

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

13179

26359

39538

52718

65897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7060

14120

21180

28240

35300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.173

AC:

26373

AN:

152182

Hom.:

2538

Cov.:

AF XY:

0.177

AC XY:

13143

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.111

AC:

4600

AN:

41538

American (AMR)

AF:

0.248

AC:

3796

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

701

AN:

3470

East Asian (EAS)

AF:

0.106

AC:

551

AN:

5184

South Asian (SAS)

AF:

0.242

AC:

1165

AN:

4822

European-Finnish (FIN)

AF:

0.232

AC:

2452

AN:

10588

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.184

AC:

12503

AN:

67988

Other (OTH)

AF:

0.180

AC:

380

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1117

2234

3350

4467

5584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.186

Hom.:

879

Bravo

AF:

0.174

Asia WGS

AF:

0.171

AC:

595

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.196

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Multiple endocrine neoplasia type 2A (2)

Multiple endocrine neoplasia, type 2 (2)

Pheochromocytoma (2)

Hirschsprung disease, susceptibility to, 1 (1)

Multiple endocrine neoplasia (1)

Multiple endocrine neoplasia type 2B (1)

Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

-0.75

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.52

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over