10-43124887-C-T

Variant names:

• chr10-43124887-C-T
• rs17158558
• NM_020975.6:c.2944C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020975.6(RET):​c.2944C>T​(p.Arg982Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,854 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R982S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (30 hom., cov: 33)
  • Exomes 𝑓: 0.016 (342 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:35 O:2
• Conservation: PhyloP100: 1.17
• Publications: 73 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009423137).
• BP6: Variant 10-43124887-C-T is Benign according to our data. Variant chr10-43124887-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13938.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0165 (2520/152304) while in subpopulation SAS AF = 0.0402 (194/4830). AF 95% confidence interval is 0.0355. There are 30 homozygotes in GnomAd4. There are 1224 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

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.2944C>T	p.Arg982Cys	missense	Exon 18 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2944C>T	p.Arg982Cys	missense	Exon 18 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2944C>T	p.Arg982Cys	missense	Exon 18 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.2944C>T	p.Arg982Cys	missense	Exon 18 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2944C>T	p.Arg982Cys	missense	Exon 18 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2680C>T	p.Arg894Cys	missense	Exon 18 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2514 AN: 152186 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.0192 AC: 4838 AN: 251460 AF XY: 0.0205

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0336

Gnomad EAS exome AF: 0.0141

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0163 AC: 23888 AN: 1461550 Hom.: 342 Cov.: 31 AF XY: 0.0171 AC XY: 12431 AN XY: 727090

African (AFR) AF: 0.0152 AC: 510 AN: 33468

American (AMR) AF: 0.0147 AC: 656 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 889 AN: 26134

East Asian (EAS) AF: 0.00796 AC: 316 AN: 39698

South Asian (SAS) AF: 0.0425 AC: 3661 AN: 86226

European-Finnish (FIN) AF: 0.00695 AC: 371 AN: 53400

Middle Eastern (MID) AF: 0.0376 AC: 210 AN: 5590

European-Non Finnish (NFE) AF: 0.0145 AC: 16154 AN: 1111940

Other (OTH) AF: 0.0186 AC: 1121 AN: 60370

GnomAD4 genome AF: 0.0165 AC: 2520 AN: 152304 Hom.: 30 Cov.: 33 AF XY: 0.0164 AC XY: 1224 AN XY: 74468

African (AFR) AF: 0.0149 AC: 621 AN: 41570

American (AMR) AF: 0.0225 AC: 344 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5174

South Asian (SAS) AF: 0.0402 AC: 194 AN: 4830

European-Finnish (FIN) AF: 0.00528 AC: 56 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1072 AN: 68030

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.0168 Hom.: 111

Bravo AF: 0.0169

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0192 AC: 2335

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0194

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (11)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Multiple endocrine neoplasia, type 2 (3)
-	-	2	Multiple endocrine neoplasia (2)
-	1	1	Multiple endocrine neoplasia type 2A (2)
-	-	2	Multiple endocrine neoplasia type 2B (2)
-	-	2	Pheochromocytoma (2)
-	1	-	Aganglionic megacolon (1)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
-	-	1	Familial medullary thyroid carcinoma (1)
-	-	1	Hirschsprung disease, susceptibility to, 1 (2)
-	-	1	Malignant tumor of breast (1)
-	-	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)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.28
Sift	Benign	0.058	T
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.088
MPC		0.88
ClinPred		0.028	T
GERP RS		-0.30
Varity_R		0.51
gMVP		0.25
Mutation Taster		=97/3	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: rs17158558; hg19: chr10-43620335; COSMIC: COSV60696488;