17-76736271-G-C

Position:

• chr17-76736271-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195427.2(SRSF2):​c.556C>G​(p.Arg186Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. R186L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRSF2 NM_001195427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.306

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22332108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRSF2	NM_001195427.2	c.556C>G	p.Arg186Gly	missense_variant	2/3	ENST00000359995.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRSF2	ENST00000359995.10	c.556C>G	p.Arg186Gly	missense_variant	2/3	1	NM_001195427.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2023

The c.556C>G (p.R186G) alteration is located in exon 2 (coding exon 2) of the SRSF2 gene. This alteration results from a C to G substitution at nucleotide position 556, causing the arginine (R) at amino acid position 186 to be replaced by a glycine (G). 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	0.31
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.67
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.82	.;.;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.019	D;.;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.80	P;P;.
Vest4		0.31
MutPred		0.34		Loss of methylation at R186 (P = 0.026);Loss of methylation at R186 (P = 0.026);.;
MVP		0.15
MPC		1.8
ClinPred		0.79	D
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-74732353;