ENST00000692848.1:c.63+22C>T

Variant names:

• chr22-50674726-C-T
• rs938259102
• NM_001372044.2:c.288+22C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000692848.2(SHANK3):​c.288+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,036,834 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00071 (3 hom.)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.97
• 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)

ENSG00000301328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-50674726-C-T is Benign according to our data. Variant chr22-50674726-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000296 (43/145290) while in subpopulation NFE AF = 0.000551 (36/65352). AF 95% confidence interval is 0.000409. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 43 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692848.2. 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.288+22C>T		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.288+22C>T		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.290+22C>T		intron	N/A
	SHANK3	ENST00000673971.3		n.288+22C>T		intron	N/A	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 43 AN: 145290 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000551

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000564 AC: 6 AN: 10638 AF XY: 0.000604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000710 AC: 633 AN: 891544 Hom.: 3 Cov.: 20 AF XY: 0.000728 AC XY: 307 AN XY: 421816

African (AFR) AF: 0.00 AC: 0 AN: 16754

American (AMR) AF: 0.00 AC: 0 AN: 4136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7300

East Asian (EAS) AF: 0.00 AC: 0 AN: 6198

South Asian (SAS) AF: 0.00 AC: 0 AN: 23432

European-Finnish (FIN) AF: 0.000377 AC: 2 AN: 5306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1904

European-Non Finnish (NFE) AF: 0.000785 AC: 625 AN: 796372

Other (OTH) AF: 0.000199 AC: 6 AN: 30142

GnomAD4 genome AF: 0.000296 AC: 43 AN: 145290 Hom.: 0 Cov.: 29 AF XY: 0.000184 AC XY: 13 AN XY: 70714

African (AFR) AF: 0.0000992 AC: 4 AN: 40332

American (AMR) AF: 0.000136 AC: 2 AN: 14740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4896

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.000116 AC: 1 AN: 8632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.000551 AC: 36 AN: 65352

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000314

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Uncertain	0.99
PhyloP100		2.0
PromoterAI		-0.075	Neutral
Mutation Taster		=100/0	polymorphism

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: rs938259102; hg19: chr22-51113154;