rs2506012

Positions:

• chr10-43080224-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_020975.6(RET):​c.73+2893C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 152,286 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.024 (61 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0238 (3625/152286) while in subpopulation NFE AF= 0.0365 (2480/68016). AF 95% confidence interval is 0.0353. There are 61 homozygotes in gnomad4. There are 1751 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 61 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.73+2893C>G		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.73+2893C>G		intron_variant		5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3622 AN: 152168 Hom.: 61 Cov.: 34

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0268

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0238 AC: 3625 AN: 152286 Hom.: 61 Cov.: 34 AF XY: 0.0235 AC XY: 1751 AN XY: 74450

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0248

Gnomad4 FIN AF: 0.0273

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0278 Hom.: 8

Bravo AF: 0.0225

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.4
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs2506012; hg19: chr10-43575672;