Genetic Variant SRRM2:p.Ser883Cys (chr16-2763176-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016333.4(SRRM2):c.2648C>G(p.Ser883Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,614,054 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 164 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 143 hom. )

Consequence

SRRM2
NM_016333.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.06

Publications

8 publications found

Variant links:

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

SRRM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016534626).

BP6

Variant 16-2763176-C-G is Benign according to our data. Variant chr16-2763176-C-G is described in ClinVar as [Benign]. Clinvar id is 720836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRM2	NM_016333.4 link	c.2648C>G	p.Ser883Cys	missense_variant	Exon 11 of 15	ENST00000301740.13	NP_057417.3	Q9UQ35-1A0A140VK53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRRM2	ENST00000301740.13 link	c.2648C>G	p.Ser883Cys	missense_variant	Exon 11 of 15	1	NM_016333.4	ENSP00000301740.8		Q9UQ35-1

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3760

AN:

152092

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0865

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00637

AC:

1600

AN:

251356

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.0878

Gnomad AMR exome

AF:

0.00388

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00251

AC:

3662

AN:

1461844

Hom.:

143

Cov.:

AF XY:

0.00207

AC XY:

1504

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0907

AC:

3036

AN:

33478

American (AMR)

AF:

0.00461

AC:

206

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1112004

Other (OTH)

AF:

0.00513

AC:

310

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

227

454

682

909

1136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0247

AC:

3764

AN:

152210

Hom.:

164

Cov.:

AF XY:

0.0237

AC XY:

1763

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0863

AC:

3583

AN:

41498

American (AMR)

AF:

0.00765

AC:

117

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68004

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

164

328

491

655

819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.0283

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0848

AC:

373

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00784

AC:

952

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Uncertain

0.55

D;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.66

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

2.1

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.9

D;.;.

REVEL

Benign

0.071

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.0020

B;.;.

Vest4

0.23

MVP

0.38

ClinPred

0.021

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.27

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over