16-2756500-G-T

Position:

• chr16-2756500-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016333.4(SRRM2):​c.136G>T​(p.Glu46*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRRM2 NM_016333.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.56

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2756500-G-T is Pathogenic according to our data. Variant chr16-2756500-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2785579.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRRM2	NM_016333.4	c.136G>T	p.Glu46*	stop_gained	2/15	ENST00000301740.13	NP_057417.3
SRRM2	XM_047433882.1	c.217G>T	p.Glu73*	stop_gained	2/10		XP_047289838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRRM2	ENST00000301740.13	c.136G>T	p.Glu46*	stop_gained	2/15	1	NM_016333.4	ENSP00000301740.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2023

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SRRM2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu46*) in the SRRM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SRRM2 are known to be pathogenic (PMID: 35567594). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.16
GERP RS		4.0

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: chr16-2806501;