ENST00000692848.2:c.1255+426G>A

Variant names:

• chr22-50685077-G-A
• rs9616816
• ENST00000692848.2:c.1255+426G>A

Variant summary

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

The ENST00000692848.2(SHANK3):​c.1255+426G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 151,646 control chromosomes in the GnomAD database, including 10,914 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 0.34 (10914 hom., cov: 29)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.972
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1255+426G>A		intron_variant	Intron 11 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.1255+426G>A		intron_variant	Intron 10 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51629 AN: 151528 Hom.: 10869 Cov.: 29

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.0817

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.274

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

GnomAD4 genome AF: 0.341 AC: 51736 AN: 151646 Hom.: 10914 Cov.: 29 AF XY: 0.345 AC XY: 25554 AN XY: 74100

African (AFR) AF: 0.576 AC: 23761 AN: 41260

American (AMR) AF: 0.397 AC: 6054 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0817 AC: 283 AN: 3464

East Asian (EAS) AF: 0.341 AC: 1746 AN: 5122

South Asian (SAS) AF: 0.223 AC: 1069 AN: 4796

European-Finnish (FIN) AF: 0.342 AC: 3604 AN: 10540

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14351 AN: 67918

Other (OTH) AF: 0.273 AC: 573 AN: 2100

Alfa AF: 0.247 Hom.: 21148

Bravo AF: 0.358

Asia WGS AF: 0.305 AC: 1060 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	0.19
DANN	Benign	0.33
PhyloP100		-0.97
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: rs9616816; hg19: chr22-51123505;