rs566877404

Variant names:

• chr22-50674573-CCG-C
• rs566877404
• NM_001372044.2:c.165+1_166-1delCG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BA1

The NM_001372044.2(SHANK3):​c.165+1_166-1delCG variant causes a splice acceptor, splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 495,308 control chromosomes in the GnomAD database, including 247,564 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 1.0 (69755 hom., cov: 0)
  • Exomes 𝑓: 1.0 (177809 hom.)
• Consequence: SHANK3 NM_001372044.2 splice_acceptor, splice_donor, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.584
• 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• schizophrenia 15

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

ENSG00000301328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09364548 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 22-50674573-CCG-C is Benign according to our data. Variant chr22-50674573-CCG-C is described in ClinVar as Benign. ClinVar VariationId is 1237741.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.165+1_166-1delCG		splice_acceptor splice_donor intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.165+1_166-1delCG		splice_acceptor splice_donor intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.166_167delCG		non_coding_transcript_exon	Exon 1 of 22
	SHANK3	ENST00000673971.3		n.165+1_166-1delCG		splice_acceptor splice_donor intron	N/A	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes AF: 1.00 AC: 139482 AN: 139490 Hom.: 69737 Cov.: 0

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD4 exome AF: 1.00 AC: 355697 AN: 355782 Hom.: 177809 AF XY: 1.00 AC XY: 168082 AN XY: 168122

African (AFR) AF: 0.999 AC: 6656 AN: 6660

American (AMR) AF: 0.998 AC: 453 AN: 454

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2228 AN: 2228

East Asian (EAS) AF: 1.00 AC: 1546 AN: 1546

South Asian (SAS) AF: 1.00 AC: 7212 AN: 7214

European-Finnish (FIN) AF: 1.00 AC: 202 AN: 202

Middle Eastern (MID) AF: 1.00 AC: 722 AN: 722

European-Non Finnish (NFE) AF: 1.00 AC: 325143 AN: 325218

Other (OTH) AF: 1.00 AC: 11535 AN: 11538

GnomAD4 genome AF: 1.00 AC: 139518 AN: 139526 Hom.: 69755 Cov.: 0 AF XY: 1.00 AC XY: 67687 AN XY: 67692

African (AFR) AF: 1.00 AC: 38432 AN: 38434

American (AMR) AF: 1.00 AC: 14470 AN: 14470

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3340 AN: 3340

East Asian (EAS) AF: 1.00 AC: 4368 AN: 4368

South Asian (SAS) AF: 1.00 AC: 4485 AN: 4486

European-Finnish (FIN) AF: 1.00 AC: 7796 AN: 7796

Middle Eastern (MID) AF: 1.00 AC: 256 AN: 256

European-Non Finnish (NFE) AF: 1.00 AC: 63583 AN: 63588

Other (OTH) AF: 1.00 AC: 1940 AN: 1940

Alfa AF: 1.00 Hom.: 8140

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs566877404; hg19: chr22-51113001;