chr10-43111279-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_020975.6(RET):c.1336G>C(p.Gly446Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,614,172 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G446S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20O:1

Conservation

PhyloP100: 0.899

Publications

7 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: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004567325).

BP6

Variant 10-43111279-G-C is Benign according to our data. Variant chr10-43111279-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00218 (332/152354) while in subpopulation AFR AF = 0.0075 (312/41588). AF 95% confidence interval is 0.00682. There are 1 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

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
RET	NM_020975.6	MANE Select	c.1336G>C	p.Gly446Arg	missense	Exon 7 of 20	NP_066124.1
RET	NM_001406743.1		c.1336G>C	p.Gly446Arg	missense	Exon 7 of 21	NP_001393672.1
RET	NM_001406744.1		c.1336G>C	p.Gly446Arg	missense	Exon 7 of 20	NP_001393673.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RET	ENST00000355710.8	TSL:5 MANE Select	c.1336G>C	p.Gly446Arg	missense	Exon 7 of 20	ENSP00000347942.3
RET	ENST00000340058.6	TSL:1	c.1336G>C	p.Gly446Arg	missense	Exon 7 of 19	ENSP00000344798.4
RET	ENST00000713926.1		c.1207G>C	p.Gly403Arg	missense	Exon 7 of 19	ENSP00000519223.1

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00755

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000589

AC:

148

AN:

251446

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000261

AC:

382

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00953

AC:

319

AN:

33480

American (AMR)

AF:

0.000537

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112002

Other (OTH)

AF:

0.000348

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00218

AC:

332

AN:

152354

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00750

AC:

312

AN:

41588

American (AMR)

AF:

0.00105

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000417

Hom.:

Bravo

AF:

0.00257

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000733

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Multiple endocrine neoplasia type 2B (2)

Multiple endocrine neoplasia, type 2 (2)

Hirschsprung disease, susceptibility to, 1 (1)

Multiple endocrine neoplasia (1)

Multiple endocrine neoplasia type 2A (1)

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)

Pheochromocytoma (1)

Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.4

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.77

M_CAP

Benign

0.072

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.1

PhyloP100

0.90

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.47

REVEL

Benign

0.15

Sift

Benign

0.058

Sift4G

Benign

0.11

Polyphen

0.76

Vest4

0.32

MVP

0.35

MPC

0.33

ClinPred

0.0052

GERP RS

2.0

Varity_R

0.091

gMVP

0.43

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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