rs745950788

chr22-50697269-TG-Tchr22-50697269-TG-TGGchr22-50697269-TG-TGGGGGGchr22-50697269-TG-TGGGGGGG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001372044.2(SHANK3):c.1528-280del 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 NM_001372044.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 1325965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK3	NM_001372044.2	c.1528-280del		intron_variant		ENST00000710353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK3	ENST00000262795.7	c.948-287del		intron_variant		5		P1
SHANK3	ENST00000673971.2	c.1305-287del		intron_variant, NMD_transcript_variant
SHANK3	ENST00000414786.7	n.1532-287del		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.00275 AC: 10 AN: 3636 Hom.: 0 AF XY: 0.00444 AC XY: 9 AN XY: 2026

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00172

Gnomad4 AMR exome AF: 0.000631

Gnomad4 ASJ exome AF: 0.000512

Gnomad4 EAS exome AF: 0.000282

Gnomad4 SAS exome AF: 0.000566

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.000864

Gnomad4 OTH exome AF: 0.000871

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000239

Gnomad4 SAS AF: 0.000257

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000640

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

- -

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;