chr4-185691521-G-A

Variant names:

• chr4-185691521-G-A
• rs4376189
• NM_001395207.1:c.-40-910C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001395207.1(SORBS2):​c.-40-910C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 152,250 control chromosomes in the GnomAD database, including 64,639 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.92 (64639 hom., cov: 31)
• Consequence: SORBS2 NM_001395207.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.718
• Publications: 6 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 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORBS2	NM_001395207.1	c.-40-910C>T		intron_variant	Intron 3 of 26	ENST00000695409.1	NP_001382136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORBS2	ENST00000695409.1	c.-40-910C>T		intron_variant	Intron 3 of 26		NM_001395207.1	ENSP00000511888.1

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140173 AN: 152132 Hom.: 64576 Cov.: 31

Gnomad AFR AF: 0.947

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.918

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.860

Gnomad NFE AF: 0.909

Gnomad OTH AF: 0.909

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.921 AC: 140295 AN: 152250 Hom.: 64639 Cov.: 31 AF XY: 0.921 AC XY: 68588 AN XY: 74438

African (AFR) AF: 0.947 AC: 39330 AN: 41544

American (AMR) AF: 0.937 AC: 14336 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 3040 AN: 3472

East Asian (EAS) AF: 0.900 AC: 4659 AN: 5174

South Asian (SAS) AF: 0.919 AC: 4418 AN: 4810

European-Finnish (FIN) AF: 0.907 AC: 9611 AN: 10600

Middle Eastern (MID) AF: 0.856 AC: 250 AN: 292

European-Non Finnish (NFE) AF: 0.909 AC: 61848 AN: 68026

Other (OTH) AF: 0.911 AC: 1926 AN: 2114

Alfa AF: 0.912 Hom.: 214185

Bravo AF: 0.925

Asia WGS AF: 0.900 AC: 3131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.043
DANN	Benign	0.49
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4376189; hg19: chr4-186612675;