22-50697269-TG-TGG

Variant names:

• chr22-50697269-T-TG
• rs745950788
• NM_001372044.2:c.1528-280dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001372044.2(SHANK3):​c.1528-280dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 240,746 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (2 hom., cov: 29)
  • Exomes 𝑓: 0.013 (2 hom.)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine
• schizophrenia 15

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 22-50697269-T-TG is Benign according to our data. Variant chr22-50697269-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 50948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00595 (801/134670) while in subpopulation NFE AF = 0.00839 (524/62482). AF 95% confidence interval is 0.00779. There are 2 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 801 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. 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
	SHANK3	NM_001372044.2	MANE Select	c.1528-280dupG		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.1530-295_1530-294insG		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.948-295_948-294insG		intron	N/A	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000414786.8	TSL:5	n.1532-295_1532-294insG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00596 AC: 802 AN: 134598 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00774

Gnomad ASJ AF: 0.00878

Gnomad EAS AF: 0.000716

Gnomad SAS AF: 0.00129

Gnomad FIN AF: 0.00335

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00840

Gnomad OTH AF: 0.00594

GnomAD2 exomes AF: 0.00523 AC: 19 AN: 3636 AF XY: 0.00642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0127 AC: 1346 AN: 106076 Hom.: 2 Cov.: 0 AF XY: 0.0126 AC XY: 678 AN XY: 53930

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

African (AFR) AF: 0.00549 AC: 16 AN: 2912

American (AMR) AF: 0.00881 AC: 28 AN: 3178

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 58 AN: 3910

East Asian (EAS) AF: 0.000281 AC: 3 AN: 10680

South Asian (SAS) AF: 0.00338 AC: 6 AN: 1774

European-Finnish (FIN) AF: 0.0107 AC: 106 AN: 9912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 704

European-Non Finnish (NFE) AF: 0.0157 AC: 1040 AN: 66100

Other (OTH) AF: 0.0129 AC: 89 AN: 6906

⚠️ 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: 0.00595 AC: 801 AN: 134670 Hom.: 2 Cov.: 29 AF XY: 0.00548 AC XY: 359 AN XY: 65452

African (AFR) AF: 0.00269 AC: 97 AN: 36006

American (AMR) AF: 0.00772 AC: 105 AN: 13594

Ashkenazi Jewish (ASJ) AF: 0.00878 AC: 28 AN: 3190

East Asian (EAS) AF: 0.000717 AC: 3 AN: 4182

South Asian (SAS) AF: 0.00129 AC: 5 AN: 3886

European-Finnish (FIN) AF: 0.00335 AC: 28 AN: 8358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00839 AC: 524 AN: 62482

Other (OTH) AF: 0.00589 AC: 11 AN: 1868

Alfa AF: 0.00120 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Phelan-McDermid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=120/80	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: COSV53187615;