NM_001372044.2:c.3118G>C

Variant names:

• chr22-50720726-G-C
• NM_001372044.2:c.3079G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001372044.2(SHANK3):​c.3079G>C​(p.Glu1027Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23195124).

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.3079G>C	p.Glu1027Gln	missense	Exon 24 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.3076G>C	p.Glu1026Gln	missense	Exon 22 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.2494G>C	p.Glu832Gln	missense	Exon 20 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.1036G>C	p.Glu346Gln	missense	Exon 5 of 6	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1134838 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 558732

African (AFR) AF: 0.00 AC: 0 AN: 20570

American (AMR) AF: 0.00 AC: 0 AN: 20718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15698

East Asian (EAS) AF: 0.00 AC: 0 AN: 12840

South Asian (SAS) AF: 0.00 AC: 0 AN: 69674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2902

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 928206

Other (OTH) AF: 0.00 AC: 0 AN: 41652

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.46	T
PhyloP100		4.7
PrimateAI	Pathogenic	0.93	D
REVEL	Benign	0.22
Sift4G	Benign	0.12	T
Vest4		0.19
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.17
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

hg19: chr22-51159154;