NM_001372044.2:c.2537-595G>C

Variant names:

• chr22-50719589-G-C
• rs6010065
• NM_001372044.2:c.2537-595G>C

Variant summary

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

The NM_001372044.2(SHANK3):​c.2537-595G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 152,008 control chromosomes in the GnomAD database, including 21,493 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 0.52 (21493 hom., cov: 32)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 5 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 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.2537-595G>C		intron	N/A	NP_001358973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.2534-595G>C		intron	N/A	ENSP00000510794.2
	SHANK3	ENST00000262795.8	TSL:5	c.1952-595G>C		intron	N/A	ENSP00000489147.3
	SHANK3	ENST00000664402.3		c.494-595G>C		intron	N/A	ENSP00000499475.2

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79123 AN: 151890 Hom.: 21443 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.521 AC: 79238 AN: 152008 Hom.: 21493 Cov.: 32 AF XY: 0.516 AC XY: 38358 AN XY: 74306

African (AFR) AF: 0.678 AC: 28130 AN: 41486

American (AMR) AF: 0.487 AC: 7435 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1283 AN: 3472

East Asian (EAS) AF: 0.545 AC: 2798 AN: 5130

South Asian (SAS) AF: 0.481 AC: 2317 AN: 4818

European-Finnish (FIN) AF: 0.448 AC: 4737 AN: 10578

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30903 AN: 67928

Other (OTH) AF: 0.489 AC: 1033 AN: 2114

Alfa AF: 0.497 Hom.: 2431

Bravo AF: 0.527

Asia WGS AF: 0.575 AC: 1998 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.30
DANN	Benign	0.48
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs6010065; hg19: chr22-51158017;