rs2341011

Variant names:

• chr22-50701207-C-T
• rs2341011
• NM_001372044.2:c.1798+2404C>T

Variant summary

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

The NM_001372044.2(SHANK3):​c.1798+2404C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,062 control chromosomes in the GnomAD database, including 8,197 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 0.31 (8197 hom., cov: 33)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.690
• Publications: 2 publications found

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

SHANK3 Gene-Disease associations (from GenCC):

• Phelan-McDermid syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• schizophrenia 15

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1798+2404C>T		intron_variant	Intron 15 of 24	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.1795+2404C>T		intron_variant	Intron 13 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46672 AN: 151944 Hom.: 8162 Cov.: 33

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.308 AC: 46764 AN: 152062 Hom.: 8197 Cov.: 33 AF XY: 0.313 AC XY: 23298 AN XY: 74324

African (AFR) AF: 0.453 AC: 18783 AN: 41452

American (AMR) AF: 0.386 AC: 5901 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 266 AN: 3466

East Asian (EAS) AF: 0.344 AC: 1779 AN: 5164

South Asian (SAS) AF: 0.246 AC: 1188 AN: 4820

European-Finnish (FIN) AF: 0.351 AC: 3713 AN: 10578

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14313 AN: 67966

Other (OTH) AF: 0.253 AC: 534 AN: 2112

Alfa AF: 0.245 Hom.: 2208

Bravo AF: 0.316

Asia WGS AF: 0.302 AC: 1050 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.70
PhyloP100		-0.69
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: rs2341011; hg19: chr22-51139635;