4-185587666-G-T

Variant summary

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

The NM_001395207.1(SORBS2):c.3864C>A(p.Phe1288Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000573 in 1,613,390 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 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: SORBS2 NM_001395207.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05460164).
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORBS2	NM_001395207.1	c.3864C>A	p.Phe1288Leu	missense_variant	27/27	ENST00000695409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORBS2	ENST00000695409.1	c.3864C>A	p.Phe1288Leu	missense_variant	27/27		NM_001395207.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000280 AC: 70 AN: 249748 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135016

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000487

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000591 AC: 864 AN: 1461150 Hom.: 0 Cov.: 30 AF XY: 0.000618 AC XY: 449 AN XY: 726782

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000693

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74438

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000546 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000818

EpiControl AF: 0.000711

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

Sep 27, 2021

The c.3264C>A (p.F1088L) alteration is located in exon 21 (coding exon 17) of the SORBS2 gene. This alteration results from a C to A substitution at nucleotide position 3264, causing the phenylalanine (F) at amino acid position 1088 to be replaced by a leucine (L). 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	0.88
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.14
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.055	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.82	D
Polyphen		0.99, 0.98	.;.;.;D;.;.;.;.;D
Vest4		0.11, 0.12, 0.12, 0.12, 0.13, 0.11
MutPred		0.30		.;.;.;Gain of MoRF binding (P = 0.1294);.;.;.;.;.;
MVP		0.35
MPC		0.29
ClinPred		0.33	T
GERP RS		3.7
Varity_R		0.24
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs112158586; hg19: chr4-186508820; COSMIC: COSV99511226; COSMIC: COSV99511226;