20-4786300-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014737.3(RASSF2):​c.842C>T​(p.Pro281Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RASSF2
NM_014737.3 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.57
Variant links:
Genes affected
RASSF2 (HGNC:9883): (Ras association domain family member 2) This gene encodes a protein that contains a Ras association domain. Similar to its cattle and sheep counterparts, this gene is located near the prion gene. Two alternatively spliced transcripts encoding the same isoform have been reported. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RASSF2NM_014737.3 linkuse as main transcriptc.842C>T p.Pro281Leu missense_variant 11/12 ENST00000379400.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RASSF2ENST00000379400.8 linkuse as main transcriptc.842C>T p.Pro281Leu missense_variant 11/121 NM_014737.3 P1P50749-1
RASSF2ENST00000379376.2 linkuse as main transcriptc.842C>T p.Pro281Leu missense_variant 10/111 P1P50749-1
RASSF2ENST00000478553.1 linkuse as main transcriptn.812C>T non_coding_transcript_exon_variant 8/91

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251458
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1460526
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
726724
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2023The c.842C>T (p.P281L) alteration is located in exon 11 (coding exon 9) of the RASSF2 gene. This alteration results from a C to T substitution at nucleotide position 842, causing the proline (P) at amino acid position 281 to be replaced by a leucine (L). 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
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;T
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Benign
0.033
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Benign
-0.98
T
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-6.8
D;D
REVEL
Uncertain
0.53
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;D
Vest4
0.93
MutPred
0.58
Gain of catalytic residue at P281 (P = 0.0098);Gain of catalytic residue at P281 (P = 0.0098);
MVP
0.67
MPC
1.2
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.67
gMVP
0.71

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.

Other links and lift over

dbSNP: rs770738940; hg19: chr20-4766946; API