dbSNP rs121434524: RNF6:p.Gly244Asp (chr13-26215151-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_005977.4(RNF6):c.731G>A(p.Gly244Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G244S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RNF6
NM_005977.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.04

Publications

2 publications found

Variant links:

Genes affected

RNF6 (HGNC:10069): (ring finger protein 6) The protein encoded by this gene contains a RING-H2 finger motif. Deletions and mutations in this gene were detected in esophageal squamous cell carcinoma (ESCC), suggesting that this protein may be a potential tumor suppressor. Studies of the mouse counterpart suggested a role of this protein in the transcription regulation that controls germinal differentiation. Multiple alternatively spliced transcript variants encoding the same protein are observed. [provided by RefSeq, Jul 2008]

RNF6 Gene-Disease associations (from GenCC):

esophageal cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

RNF6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-26215151-C-T is Pathogenic according to our data. Variant chr13-26215151-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5702.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.24302882). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005977.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF6	NM_005977.4	MANE Select	c.731G>A	p.Gly244Asp	missense	Exon 5 of 5	NP_005968.1	A0A024RDP2
RNF6	NM_183043.3		c.731G>A	p.Gly244Asp	missense	Exon 5 of 5	NP_898864.1	Q9Y252-1
RNF6	NM_183044.3		c.731G>A	p.Gly244Asp	missense	Exon 5 of 5	NP_898865.1	Q9Y252-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF6	ENST00000381588.9	TSL:1 MANE Select	c.731G>A	p.Gly244Asp	missense	Exon 5 of 5	ENSP00000371000.4	Q9Y252-1
RNF6	ENST00000346166.7	TSL:1	c.731G>A	p.Gly244Asp	missense	Exon 5 of 5	ENSP00000342121.3	Q9Y252-1
RNF6	ENST00000381570.7	TSL:1	c.731G>A	p.Gly244Asp	missense	Exon 5 of 5	ENSP00000370982.3	Q9Y252-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Esophageal squamous cell carcinoma, somatic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.54

M_CAP

Benign

0.0088

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PhyloP100

5.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.090

REVEL

Benign

0.079

Sift

Uncertain

0.0010

Sift4G

Benign

0.41

Polyphen

0.016

Vest4

0.56

MutPred

0.25

Loss of MoRF binding (P = 0.0533)

MVP

0.38

MPC

0.87

ClinPred

0.87

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.37

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over