rs10451

Variant names:

• chr22-50723631-G-A
• rs10451
• NM_001372044.2:c.4790+1194G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-50723631-G-A
• chr22-50723631-G-C
• chr22-50723631-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372044.2(SHANK3):​c.4790+1194G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,064 control chromosomes in the GnomAD database, including 9,741 homozygotes. 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: 𝑓 0.35 (9741 hom., cov: 32)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 4 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: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• schizophrenia 15

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.4790+1194G>A		intron	N/A	NP_001358973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.4787+1194G>A		intron	N/A	ENSP00000510794.2
	SHANK3	ENST00000262795.8	TSL:5	c.4205+1194G>A		intron	N/A	ENSP00000489147.3
	SHANK3	ENST00000664402.3		c.2747+1194G>A		intron	N/A	ENSP00000499475.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53085 AN: 151946 Hom.: 9721 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.339

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.350 AC: 53157 AN: 152064 Hom.: 9741 Cov.: 32 AF XY: 0.350 AC XY: 26002 AN XY: 74326

African (AFR) AF: 0.450 AC: 18640 AN: 41454

American (AMR) AF: 0.319 AC: 4877 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3472

East Asian (EAS) AF: 0.441 AC: 2285 AN: 5178

South Asian (SAS) AF: 0.361 AC: 1740 AN: 4818

European-Finnish (FIN) AF: 0.347 AC: 3661 AN: 10564

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.296 AC: 20151 AN: 67990

Other (OTH) AF: 0.344 AC: 724 AN: 2104

Alfa AF: 0.313 Hom.: 25904

Bravo AF: 0.351

Asia WGS AF: 0.448 AC: 1553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.1
DANN	Benign	0.68
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10451; hg19: chr22-51162059;