22-50675029-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000262795.7(SHANK3):c.-313C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,524,478 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (8 hom.)
• Consequence: SHANK3 ENST00000262795.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.934

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-50675029-C-G is Benign according to our data. Variant chr22-50675029-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1253739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK3	NM_001372044.2	c.289-19C>G		intron_variant		ENST00000710353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK3	ENST00000262795.7	c.-313C>G		5_prime_UTR_variant	1/22	5		P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 235 AN: 151018 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000489

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000975 AC: 122 AN: 125174 Hom.: 2 AF XY: 0.000990 AC XY: 68 AN XY: 68678

Gnomad AFR exome AF: 0.000173

Gnomad AMR exome AF: 0.0000833

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000696

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000260

GnomAD4 exome AF: 0.000552 AC: 758 AN: 1373346 Hom.: 8 Cov.: 31 AF XY: 0.000534 AC XY: 361 AN XY: 676430

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000511

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.000490

GnomAD4 genome AF: 0.00155 AC: 235 AN: 151132 Hom.: 1 Cov.: 31 AF XY: 0.00242 AC XY: 179 AN XY: 73818

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.000489

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000546 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.2
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757516415; hg19: chr22-51113457;