ENST00000692848.2:c.1530-294delG

Variant names:

• chr22-50697269-TG-T
• rs745950788
• ENST00000692848.2:c.1530-294delG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The ENST00000692848.2(SHANK3):​c.1530-294delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 240,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.94
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 22-50697269-TG-T is Benign according to our data. Variant chr22-50697269-TG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1325965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1528-280delG		intron_variant	Intron 12 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.1530-294delG		intron_variant	Intron 11 of 22			ENSP00000510794.2
SHANK3	ENST00000262795.8	c.948-294delG		intron_variant	Intron 9 of 20	5		ENSP00000489147.3
SHANK3	ENST00000414786.8	n.1532-294delG		intron_variant	Intron 10 of 21	5
SHANK3	ENST00000673971.3	n.1530-294delG		intron_variant	Intron 11 of 22			ENSP00000501192.2

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 6 AN: 134606 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000239

Gnomad SAS AF: 0.000257

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000640

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00275 AC: 10 AN: 3636 AF XY: 0.00444

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0172

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000869 AC: 92 AN: 105838 Hom.: 0 Cov.: 0 AF XY: 0.000818 AC XY: 44 AN XY: 53800

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00172 AC: 5 AN: 2902

American (AMR) AF: 0.000631 AC: 2 AN: 3170

Ashkenazi Jewish (ASJ) AF: 0.000512 AC: 2 AN: 3904

East Asian (EAS) AF: 0.000282 AC: 3 AN: 10638

South Asian (SAS) AF: 0.000566 AC: 1 AN: 1768

European-Finnish (FIN) AF: 0.00162 AC: 16 AN: 9882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 700

European-Non Finnish (NFE) AF: 0.000864 AC: 57 AN: 65982

Other (OTH) AF: 0.000871 AC: 6 AN: 6892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000446 AC: 6 AN: 134606 Hom.: 0 Cov.: 29 AF XY: 0.0000612 AC XY: 4 AN XY: 65390

African (AFR) AF: 0.00 AC: 0 AN: 35934

American (AMR) AF: 0.00 AC: 0 AN: 13576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3190

East Asian (EAS) AF: 0.000239 AC: 1 AN: 4190

South Asian (SAS) AF: 0.000257 AC: 1 AN: 3884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.0000640 AC: 4 AN: 62490

Other (OTH) AF: 0.00 AC: 0 AN: 1852

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 20, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=113/87	disease causing (fs/PTC)

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: rs745950788; hg19: chr22-51135697; COSMIC: COSV53182926;