chr17-76736323-C-G

Variant names:

• chr17-76736323-C-G
• rs376398460
• NM_001195427.2:c.504G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001195427.2(SRSF2):​c.504G>C​(p.Arg168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R168R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SRSF2 NM_001195427.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751
• Publications: 2 publications found

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]

ENSG00000267168 (HGNC:):

MFSD11 (HGNC:25458): (major facilitator superfamily domain containing 11) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MIR636 (HGNC:32892): (microRNA 636) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.7085 (below the threshold of 3.09). Trascript score misZ: 3.8222 (above the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.12240985).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195427.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRSF2	NM_001195427.2	MANE Select	c.504G>C	p.Arg168Ser	missense	Exon 2 of 3	NP_001182356.1	Q01130-1
	SRSF2	NM_003016.5		c.504G>C	p.Arg168Ser	missense	Exon 2 of 2	NP_003007.2
	SRSF2	NR_036608.2		n.675G>C		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRSF2	ENST00000359995.10	TSL:1 MANE Select	c.504G>C	p.Arg168Ser	missense	Exon 2 of 3	ENSP00000353089.5	Q01130-1
	SRSF2	ENST00000392485.2	TSL:1	c.504G>C	p.Arg168Ser	missense	Exon 2 of 2	ENSP00000376276.2	Q01130-1
	ENSG00000267168	ENST00000587459.1	TSL:5	c.239-1959C>G		intron	N/A	ENSP00000466829.1	K7EN84

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.9
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.75
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.34	T
Sift4G	Uncertain	0.037	D
Polyphen		0.86	P
Vest4		0.14
MutPred		0.32		Gain of phosphorylation at R168 (P = 0)
MVP		0.095
MPC		1.6
ClinPred		0.93	D
GERP RS		-10
PromoterAI		-0.042	Neutral
Varity_R		0.11
gMVP		0.69
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs376398460; hg19: chr17-74732405;