rs975392090

Variant names:

• chr22-50720576-C-G
• rs975392090
• NM_001372044.2:c.2929C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-50720576-C-G
• chr22-50720576-C-T

Variant summary

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

The NM_001372044.2(SHANK3):​c.2929C>G​(p.Pro977Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,093,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2702283).

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.2929C>G	p.Pro977Ala	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.2926C>G	p.Pro976Ala	missense	Exon 22 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.2344C>G	p.Pro782Ala	missense	Exon 20 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.886C>G	p.Pro296Ala	missense	Exon 5 of 6	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146400 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 2 AN: 947228 Hom.: 0 Cov.: 33 AF XY: 0.00000443 AC XY: 2 AN XY: 451422

African (AFR) AF: 0.000117 AC: 2 AN: 17064

American (AMR) AF: 0.00 AC: 0 AN: 3546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8398

East Asian (EAS) AF: 0.00 AC: 0 AN: 9536

South Asian (SAS) AF: 0.00 AC: 0 AN: 31636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828682

Other (OTH) AF: 0.00 AC: 0 AN: 32722

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146400 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 1 AN XY: 71198

African (AFR) AF: 0.0000490 AC: 2 AN: 40850

American (AMR) AF: 0.00 AC: 0 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65864

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.021	D
PhyloP100		3.5
PrimateAI	Pathogenic	0.92	D
REVEL	Benign	0.21
Sift4G	Uncertain	0.037	D
Vest4		0.34
GERP RS		4.4
gMVP		0.14
Mutation Taster		=72/28	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

dbSNP: rs975392090; hg19: chr22-51159004;