NM_001372044.2:c.5107C>A

Variant names:

• chr22-50730998-C-A
• rs2083360139
• NM_001372044.2:c.5068C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001372044.2(SHANK3):​c.5068C>A​(p.Arg1690Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.427
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50730998-C-A is Pathogenic according to our data. Variant chr22-50730998-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 975165.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1877962). . Strength limited to SUPPORTING due to the PP5.

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.5068C>A	p.Arg1690Ser	missense	Exon 25 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.5065C>A	p.Arg1689Ser	missense	Exon 23 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.4483C>A	p.Arg1495Ser	missense	Exon 21 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.3025C>A	p.Arg1009Ser	missense	Exon 6 of 6	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1063804 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 508898

African (AFR) AF: 0.00 AC: 0 AN: 20290

American (AMR) AF: 0.00 AC: 0 AN: 6828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11960

East Asian (EAS) AF: 0.00 AC: 0 AN: 19454

South Asian (SAS) AF: 0.00 AC: 0 AN: 31422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 905386

Other (OTH) AF: 0.00 AC: 0 AN: 40720

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Phelan-McDermid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Benign	0.88
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.43
PrimateAI	Pathogenic	0.94	D
REVEL	Benign	0.12
Sift4G	Benign	0.72	T
Vest4		0.48
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.37
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2083360139; hg19: chr22-51169426;