4-185593896-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001395207.1(SORBS2):c.3724G>T(p.Gly1242Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,603,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: SORBS2 NM_001395207.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87

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

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042839676).
• BS2: High AC in GnomAd at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORBS2	NM_001395207.1	c.3724G>T	p.Gly1242Trp	missense_variant	25/27	ENST00000695409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORBS2	ENST00000695409.1	c.3724G>T	p.Gly1242Trp	missense_variant	25/27		NM_001395207.1
SORBS2-AS1	ENST00000411847.1	n.1682C>A		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000327 AC: 82 AN: 251146 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000227 AC: 330 AN: 1451266 Hom.: 0 Cov.: 26 AF XY: 0.000226 AC XY: 163 AN XY: 722786

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00318

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.3124G>T (p.G1042W) alteration is located in exon 19 (coding exon 15) of the SORBS2 gene. This alteration results from a G to T substitution at nucleotide position 3124, causing the glycine (G) at amino acid position 1042 to be replaced by a tryptophan (W). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.043	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.
Vest4		0.70, 0.62, 0.66, 0.68, 0.68, 0.69, 0.68
MVP		0.50
MPC		0.83
ClinPred		0.18	T
GERP RS		5.1
Varity_R		0.74
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs141463006; hg19: chr4-186515050;