22-50674689-G-A

Variant names:

• chr22-50674689-G-A
• NM_001372044.2:c.273G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001372044.2(SHANK3):​c.273G>A​(p.Pro91Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 953,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.23
• Publications: 0 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)

ENSG00000301328 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-50674689-G-A is Benign according to our data. Variant chr22-50674689-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2653409.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.

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.273G>A	p.Pro91Pro	synonymous	Exon 3 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.273G>A	p.Pro91Pro	synonymous	Exon 2 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.275G>A		non_coding_transcript_exon	Exon 1 of 22
	SHANK3	ENST00000673971.3		n.273G>A		non_coding_transcript_exon	Exon 2 of 23	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 953006 Hom.: 0 Cov.: 29 AF XY: 0.00000218 AC XY: 1 AN XY: 457984

African (AFR) AF: 0.00 AC: 0 AN: 18208

American (AMR) AF: 0.00 AC: 0 AN: 12472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10308

East Asian (EAS) AF: 0.00 AC: 0 AN: 6084

South Asian (SAS) AF: 0.00 AC: 0 AN: 38810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2114

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825208

Other (OTH) AF: 0.0000308 AC: 1 AN: 32460

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.98
PhyloP100		-1.2
PromoterAI		-0.032	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr22-51113117;