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GeneBe

17-76736270-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001195427.2(SRSF2):c.557G>T(p.Arg186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SRSF2
NM_001195427.2 missense

Scores

1
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35
Variant links:
Genes affected
SRSF2 (HGNC:10783): (serine and arginine rich splicing factor 2) The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. Each of these factors contains an RNA recognition motif (RRM) for binding RNA and an RS domain for binding other proteins. The RS domain is rich in serine and arginine residues and facilitates interaction between different SR splicing factors. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation. Two transcript variants encoding the same protein and one non-coding transcript variant have been found for this gene. In addition, a pseudogene of this gene has been found on chromosome 11. [provided by RefSeq, Sep 2010]
MFSD11 (HGNC:25458): (major facilitator superfamily domain containing 11) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant where missense usually causes diseases, SRSF2
BP4
Computational evidence support a benign effect (MetaRNN=0.20164248).
BS2
High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SRSF2NM_001195427.2 linkuse as main transcriptc.557G>T p.Arg186Leu missense_variant 2/3 ENST00000359995.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SRSF2ENST00000359995.10 linkuse as main transcriptc.557G>T p.Arg186Leu missense_variant 2/31 NM_001195427.2 P1Q01130-1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000104
AC:
26
AN:
251192
Hom.:
1
AF XY:
0.0000884
AC XY:
12
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.000211
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000268
AC:
392
AN:
1461870
Hom.:
0
Cov.:
29
AF XY:
0.000267
AC XY:
194
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
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:
0.000346
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000270
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000327
EpiControl
AF:
0.000178

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 GeneticsFeb 15, 2023The c.557G>T (p.R186L) alteration is located in exon 2 (coding exon 2) of the SRSF2 gene. This alteration results from a G to T substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 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
Uncertain
0.36
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
26
DANN
Benign
0.69
DEOGEN2
Benign
0.37
T;T;.
Eigen
Benign
-0.0013
Eigen_PC
Benign
-0.070
FATHMM_MKL
Uncertain
0.79
D
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
2.0
M;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-2.1
N;.;.
REVEL
Benign
0.17
Sift
Uncertain
0.024
D;.;.
Sift4G
Benign
0.078
T;T;D
Polyphen
0.80
P;P;.
Vest4
0.32
MVP
0.31
MPC
1.8
ClinPred
0.15
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.29
gMVP
0.60

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: rs145534754; hg19: chr17-74732352; API