chr16-2763176-C-A

Variant names:

• chr16-2763176-C-A
• rs17136053
• NM_016333.4:c.2648C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016333.4(SRRM2):​c.2648C>A​(p.Ser883Tyr) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S883C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SRRM2 NM_016333.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 8 publications found

Genes affected

SRRM2 (HGNC:16639): (serine/arginine repetitive matrix 2) Enables C2H2 zinc finger domain binding activity and protein N-terminus binding activity. Involved in mRNA splicing, via spliceosome. Located in Cajal body and nuclear speck. Part of U2-type catalytic step 2 spliceosome and U2-type precatalytic spliceosome. Biomarker of Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

SRRM2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal dominant 72

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13669702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRM2	NM_016333.4	c.2648C>A	p.Ser883Tyr	missense_variant	Exon 11 of 15	ENST00000301740.13	NP_057417.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRRM2	ENST00000301740.13	c.2648C>A	p.Ser883Tyr	missense_variant	Exon 11 of 15	1	NM_016333.4	ENSP00000301740.8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T;.;T
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;.;.
REVEL	Benign	0.053
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.61	P;.;.
Vest4		0.33
MutPred		0.21		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;
MVP		0.40
ClinPred		0.39	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.30

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: rs17136053; hg19: chr16-2813177;