chr22-50674428-G-GCGCCGC

Position:

• chr22-50674428-G-GCGCCGC

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001372044.2(SHANK3):​c.34_39dup​(p.Ala12_Ala13dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.23

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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372044.2
• BP6: Variant 22-50674428-G-GCGCCGC is Benign according to our data. Variant chr22-50674428-G-GCGCCGC is described in ClinVar as [Likely_benign]. Clinvar id is 2672916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.34_39dup	p.Ala12_Ala13dup	inframe_insertion	2/25	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.1	c.-194_-189dup		5_prime_UTR_variant	1/10			ENSP00000510794
SHANK3	ENST00000414786.7	n.34_39dup		non_coding_transcript_exon_variant	1/23	5
SHANK3	ENST00000673971.2	c.-194_-189dup		5_prime_UTR_variant, NMD_transcript_variant	1/23			ENSP00000501192

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 20 AN: 131648 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000243

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000197

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000898 AC: 1 AN: 11130 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000152 AC: 20 AN: 131648 Hom.: 0 Cov.: 20 AF XY: 0.000189 AC XY: 12 AN XY: 63636

Gnomad4 AFR AF: 0.000140

Gnomad4 AMR AF: 0.000148

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000243

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000197

Gnomad4 OTH AF: 0.00

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

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

SHANK3: BS1 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs975668627; hg19: chr22-51112856;