9-129010209-C-G

Variant names:

• chr9-129010209-C-G
• rs762121606
• NM_020145.4:c.649G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020145.4(SH3GLB2):​c.649G>C​(p.Ala217Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3GLB2 NM_020145.4 missense, splice_region
• Scores: Splicing: ADA: 0.9733
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3GLB2	NM_020145.4	c.649G>C	p.Ala217Pro	missense_variant, splice_region_variant	Exon 8 of 11	ENST00000372564.8	NP_064530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3GLB2	ENST00000372564.8	c.649G>C	p.Ala217Pro	missense_variant, splice_region_variant	Exon 8 of 11	1	NM_020145.4	ENSP00000361645.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249290 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.649G>C (p.A217P) alteration is located in exon 8 (coding exon 8) of the SH3GLB2 gene. This alteration results from a G to C substitution at nucleotide position 649, causing the alanine (A) at amino acid position 217 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.9	M;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.99	D;D;P;.;.
Vest4		0.75
MutPred		0.62		Gain of disorder (P = 0.1051);Gain of disorder (P = 0.1051);.;Gain of disorder (P = 0.1051);.;
MVP		0.66
MPC		1.1
ClinPred		0.94	D
GERP RS		3.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.82
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762121606; hg19: chr9-131772488;