Genetic Variant NM_020145.4:c.616G>T (chr9-129012244-C-A) – 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>T(p.Ala206Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000876 in 1,141,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A206T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

SH3GLB2
NM_020145.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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.616G>T	p.Ala206Ser	missense	Exon 6 of 11	NP_064530.1	Q9NR46-1
SH3GLB2	NM_001438434.1		c.616G>T	p.Ala206Ser	missense	Exon 6 of 11	NP_001425363.1
SH3GLB2	NM_001369913.1		c.661G>T	p.Ala221Ser	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>T	p.Ala206Ser	missense	Exon 6 of 11	ENSP00000361645.3	Q9NR46-1
SH3GLB2	ENST00000372554.8	TSL:1	c.628G>T	p.Ala210Ser	missense	Exon 7 of 13	ENSP00000361634.4	Q9NR46-2
SH3GLB2	ENST00000372559.5	TSL:1	c.616G>T	p.Ala206Ser	missense	Exon 6 of 12	ENSP00000361640.1	Q9NR46-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.76e-7

AC:

AN:

1141706

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

544134

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

0.00

AC:

AN:

29192

South Asian (SAS)

AF:

0.00

AC:

AN:

26922

European-Finnish (FIN)

AF:

0.0000259

AC:

AN:

38598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4590

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

945718

Other (OTH)

AF:

0.00

AC:

AN:

45890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

7.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.23

REVEL

Benign

0.22

Sift

Benign

0.25

Sift4G

Benign

0.43

Polyphen

0.66

Vest4

0.60

MutPred

0.60

Gain of disorder (P = 0.0473)

MVP

0.36

MPC

0.91

ClinPred

0.83

GERP RS

5.8

Varity_R

0.11

gMVP

0.35

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over