Genetic Variant SORBS2:p.Gly1241Ser (chr4-185593899-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001395207.1(SORBS2):c.3721G>A(p.Gly1241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,454,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SORBS2
NM_001395207.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36

Variant links:

Genes affected

SORBS2 (HGNC:24098): (sorbin and SH3 domain containing 2) Arg and c-Abl represent the mammalian members of the Abelson family of non-receptor protein-tyrosine kinases. They interact with the Arg/Abl binding proteins via the SH3 domains present in the carboxy end of the latter group of proteins. This gene encodes the sorbin and SH3 domain containing 2 protein. It has three C-terminal SH3 domains and an N-terminal sorbin homology (SoHo) domain that interacts with lipid raft proteins. The subcellular localization of this protein in epithelial and cardiac muscle cells suggests that it functions as an adapter protein to assemble signaling complexes in stress fibers, and that it is a potential link between Abl family kinases and the actin cytoskeleton. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

SORBS2 links:

SORBS2-AS1 (HGNC:41039): (SORBS2 antisense RNA 1)

SORBS2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.065946996).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORBS2	NM_001395207.1 link	c.3721G>A	p.Gly1241Ser	missense_variant	Exon 25 of 27	ENST00000695409.1	NP_001382136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS2	ENST00000695409.1 link	c.3721G>A	p.Gly1241Ser	missense_variant	Exon 25 of 27		NM_001395207.1	ENSP00000511888.1		A0A8Q3WKK4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251254

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135802

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000619

AC:

AN:

1454596

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000724

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3121G>A (p.G1041S) alteration is located in exon 19 (coding exon 15) of the SORBS2 gene. This alteration results from a G to A substitution at nucleotide position 3121, causing the glycine (G) at amino acid position 1041 to be replaced by a serine (S). 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

Benign

0.087

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.049

.;.;.;T;.;.;.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.066

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

.;.;.;N;.;.;.;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

.;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.092

.;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.48

.;T;T;T;T;T;T;T;T;.

Polyphen

0.010, 1.0

.;.;.;B;.;.;.;.;D;.

Vest4

0.27, 0.30, 0.27, 0.30, 0.32, 0.32, 0.32, 0.33

MutPred

0.20

.;.;.;Gain of glycosylation at G1041 (P = 0.0452);.;.;.;.;.;.;

MVP

0.39

MPC

0.20

ClinPred

0.20

GERP RS

3.4

Varity_R

0.090

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over