Genetic Variant NM_020145.4:c.616G>A (chr9-129012244-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.616G>A(p.Ala206Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,293,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 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:

Genome browser will be placed here

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.616G>A	p.Ala206Thr	missense	Exon 6 of 11	NP_064530.1	Q9NR46-1
SH3GLB2	NM_001438434.1		c.616G>A	p.Ala206Thr	missense	Exon 6 of 11	NP_001425363.1
SH3GLB2	NM_001369913.1		c.661G>A	p.Ala221Thr	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.616G>A	p.Ala206Thr	missense	Exon 6 of 11	ENSP00000361645.3	Q9NR46-1
SH3GLB2	ENST00000372554.8	TSL:1	c.628G>A	p.Ala210Thr	missense	Exon 7 of 13	ENSP00000361634.4	Q9NR46-2
SH3GLB2	ENST00000372559.5	TSL:1	c.616G>A	p.Ala206Thr	missense	Exon 6 of 12	ENSP00000361640.1	Q9NR46-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151852

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:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

63988

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000210

AC:

AN:

1141706

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

544134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24608

American (AMR)

AF:

0.00

AC:

AN:

11252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14936

East Asian (EAS)

AF:

0.000137

AC:

AN:

29192

South Asian (SAS)

AF:

0.0000371

AC:

AN:

26922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4590

European-Non Finnish (NFE)

AF:

0.0000201

AC:

AN:

945718

Other (OTH)

AF:

0.00

AC:

AN:

45890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000132

AC:

AN:

151852

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41320

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000869

AC:

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

0.38

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.70

REVEL

Benign

0.23

Sift

Benign

0.26

Sift4G

Benign

0.40

Polyphen

0.81

Vest4

0.77

MutPred

0.60

Gain of helix (P = 0.0696)

MVP

0.45

MPC

0.93

ClinPred

0.86

GERP RS

5.8

Varity_R

0.12

gMVP

0.42

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over