4-185615076-C-T

Variant summary

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

The NM_001395207.1(SORBS2):c.3323G>A(p.Arg1108Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SORBS2 NM_001395207.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 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/exons	MANE	UniProt
SORBS2	NM_001395207.1	c.3323G>A	p.Arg1108Lys	missense_variant	22/27	ENST00000695409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORBS2	ENST00000695409.1	c.3323G>A	p.Arg1108Lys	missense_variant	22/27		NM_001395207.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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

Jul 09, 2021

The c.2723G>A (p.R908K) alteration is located in exon 16 (coding exon 12) of the SORBS2 gene. This alteration results from a G to A substitution at nucleotide position 2723, causing the arginine (R) at amino acid position 908 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;T;D;T;T;T;D;T;T;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N;D;N;D;D;D;N;D;D;N
REVEL	Benign	0.15
Sift	Benign	0.089	T;D;T;D;D;D;T;D;D;D
Sift4G	Benign	0.077	T;D;T;D;D;D;T;D;.;D
Polyphen		0.25, 0.97	.;.;B;.;.;.;.;D;.;.
Vest4		0.45
MutPred		0.60		.;.;Gain of methylation at R908 (P = 0.0333);.;.;.;.;.;.;.;
MVP		0.49
MPC		0.68
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.46
gMVP		0.62

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: rs2096607593; hg19: chr4-186536230;