4-185593893-C-T

Variant names:

• chr4-185593893-C-T
• rs558697505
• NM_001395207.1:c.3727G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001395207.1(SORBS2):​c.3727G>A​(p.Gly1243Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,449,726 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SORBS2 NM_001395207.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.43
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395207.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORBS2	NM_001395207.1	MANE Select	c.3727G>A	p.Gly1243Arg	missense	Exon 25 of 27	NP_001382136.1	A0A8Q3WKK4
	SORBS2	NM_001394245.1		c.3685G>A	p.Gly1229Arg	missense	Exon 23 of 25	NP_001381174.1
	SORBS2	NM_001394246.1		c.3628G>A	p.Gly1210Arg	missense	Exon 22 of 24	NP_001381175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORBS2	ENST00000695409.1	MANE Select	c.3727G>A	p.Gly1243Arg	missense	Exon 25 of 27	ENSP00000511888.1	A0A8Q3WKK4
	SORBS2	ENST00000284776.11	TSL:1	c.3127G>A	p.Gly1043Arg	missense	Exon 19 of 21	ENSP00000284776.7	O94875-1
	SORBS2	ENST00000437304.6	TSL:1	c.2299G>A	p.Gly767Arg	missense	Exon 21 of 23	ENSP00000396008.2	O94875-10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449726 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 722072

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 85938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101002

Other (OTH) AF: 0.00 AC: 0 AN: 60018

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.12	T
Polyphen		0.95	P
Vest4		0.90
MutPred		0.41		Gain of solvent accessibility (P = 0.1319)
MVP		0.57
MPC		0.81
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.66
gMVP		0.68
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs558697505; hg19: chr4-186515047;