22-50697269-TG-TGG

Position:

• chr22-50697269-TG-TGG

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 801 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1528-280dupG		intron_variant			NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7	c.948-287dupG		intron_variant		5		ENSP00000489147.3
SHANK3	ENST00000414786.7	n.1532-287dupG		intron_variant		5
SHANK3	ENST00000673971.2	n.1305-287dupG		intron_variant				ENSP00000501192.2

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

GnomAD3 exomes AF: 0.00523 AC: 19 AN: 3636 Hom.: 0 AF XY: 0.00642 AC XY: 13 AN XY: 2026

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 SAS 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

Gnomad4 AFR exome AF: 0.00549

Gnomad4 AMR exome AF: 0.00881

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.000281

Gnomad4 SAS exome AF: 0.00338

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.00595 AC: 801 AN: 134670 Hom.: 2 Cov.: 29 AF XY: 0.00548 AC XY: 359 AN XY: 65452

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.00878

Gnomad4 EAS AF: 0.000717

Gnomad4 SAS AF: 0.00129

Gnomad4 FIN AF: 0.00335

Gnomad4 NFE AF: 0.00839

Gnomad4 OTH AF: 0.00589

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	SHANK3: BS1 -

Phelan-McDermid syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs745950788; hg19: chr22-51135697;