Genetic Variant NM_001271186.2:c.466C>G (chrX-132214254-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001271186.2(RAP2C):c.466C>G(p.Leu156Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,210,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000017 ( 0 hom. 5 hem. )

Consequence

RAP2C
NM_001271186.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63

Variant links:

Genes affected

RAP2C (HGNC:21165): (RAP2C, member of RAS oncogene family) The protein encoded by this gene is a member of the Ras-related protein subfamily of the Ras GTPase superfamily. Members of this family are small GTPases that act as molecular switches to regulate cellular proliferation, differentiation, and apoptosis. This protein has been reported to activate in vitro transcriptional activity of the serum response element. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

RAP2C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20380092).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP2C	NM_001271186.2 link	c.466C>G	p.Leu156Val	missense_variant	Exon 5 of 6	ENST00000370874.2	NP_001258115.1	Q9Y3L5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAP2C	ENST00000370874.2 link	c.466C>G	p.Leu156Val	missense_variant	Exon 5 of 6	2	NM_001271186.2	ENSP00000359911.1	Q9Y3L5
RAP2C	ENST00000342983.6 link	c.466C>G	p.Leu156Val	missense_variant	Exon 3 of 4	1		ENSP00000340274.2	Q9Y3L5
RAP2C	ENST00000620646.4 link	c.268C>G	p.Leu90Val	missense_variant	Exon 5 of 6	5		ENSP00000484870.1	A0A087X2C3
RAP2C	ENST00000460462.1 link	n.545C>G		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

112093

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34263

show subpopulations

Gnomad AFR

AF:

0.000617

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000491

AC:

AN:

183354

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67816

show subpopulations

Gnomad AFR exome

AF:

0.000684

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1098122

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363486

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000170

AC:

AN:

112093

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34263

show subpopulations

Gnomad4 AFR

AF:

0.000617

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.466C>G (p.L156V) alteration is located in exon 3 (coding exon 2) of the RAP2C gene. This alteration results from a C to G substitution at nucleotide position 466, causing the leucine (L) at amino acid position 156 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.22

.;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

-0.99

.;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.49

.;N;N

REVEL

Uncertain

0.39

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0050

.;B;B

Vest4

0.56

MVP

0.86

MPC

1.2

ClinPred

0.14

GERP RS

5.6

Varity_R

0.40

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over