Genetic Variant SH3GLB2:p.Arg196Lys (chr9-129012273-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020145.4(SH3GLB2):c.587G>A(p.Arg196Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,303,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

SH3GLB2
NM_020145.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90

Publications

0 publications found

Variant links:

Genes affected

SH3GLB2 (HGNC:10834): (SH3 domain containing GRB2 like, endophilin B2) Enables identical protein binding activity. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SH3GLB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020145.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3GLB2	NM_020145.4	MANE Select	c.587G>A	p.Arg196Lys	missense	Exon 6 of 11	NP_064530.1	Q9NR46-1
SH3GLB2	NM_001438434.1		c.587G>A	p.Arg196Lys	missense	Exon 6 of 11	NP_001425363.1
SH3GLB2	NM_001369913.1		c.632G>A	p.Arg211Lys	missense	Exon 7 of 13	NP_001356842.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3GLB2	ENST00000372564.8	TSL:1 MANE Select	c.587G>A	p.Arg196Lys	missense	Exon 6 of 11	ENSP00000361645.3	Q9NR46-1
SH3GLB2	ENST00000372554.8	TSL:1	c.599G>A	p.Arg200Lys	missense	Exon 7 of 13	ENSP00000361634.4	Q9NR46-2
SH3GLB2	ENST00000372559.5	TSL:1	c.587G>A	p.Arg196Lys	missense	Exon 6 of 12	ENSP00000361640.1	Q9NR46-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.68e-7

AC:

AN:

1151768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

550160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24768

American (AMR)

AF:

0.00

AC:

AN:

12778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15040

East Asian (EAS)

AF:

0.00

AC:

AN:

29582

South Asian (SAS)

AF:

0.00

AC:

AN:

27606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4652

European-Non Finnish (NFE)

AF:

0.00000105

AC:

AN:

951076

Other (OTH)

AF:

0.00

AC:

AN:

46296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

0.0079

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.7

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.61

REVEL

Benign

0.21

Sift

Benign

0.20

Sift4G

Benign

0.71

Polyphen

0.20

Vest4

0.72

MutPred

0.48

Gain of ubiquitination at R196 (P = 0.0069)

MVP

0.50

MPC

0.95

ClinPred

0.88

GERP RS

5.8

Varity_R

0.18

gMVP

0.46

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -28

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over