22-50674428-GCGC-G

Variant names:

• chr22-50674428-GCGC-G
• rs975668627
• ENST00000692848:c.-191_-189delGCC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_001372044.2(SHANK3):​c.37_39delGCC​(p.Ala13del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 142,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0099 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19

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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372044.2
• BP6: Variant 22-50674428-GCGC-G is Benign according to our data. Variant chr22-50674428-GCGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 2498915.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00993 (103/10368) while in subpopulation MID AF= 0.04 (2/50). AF 95% confidence interval is 0.011. There are 0 homozygotes in gnomad4_exome. There are 70 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.37_39delGCC	p.Ala13del	conservative_inframe_deletion	Exon 2 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848	c.-191_-189delGCC		5_prime_UTR_variant	Exon 1 of 10			ENSP00000510794.2
SHANK3	ENST00000414786.7	n.37_39delGCC		non_coding_transcript_exon_variant	Exon 1 of 23	5
SHANK3	ENST00000673971.2	n.-191_-189delGCC		non_coding_transcript_exon_variant	Exon 1 of 23			ENSP00000501192.2
SHANK3	ENST00000673971.2	n.-191_-189delGCC		5_prime_UTR_variant	Exon 1 of 23			ENSP00000501192.2

Frequencies

GnomAD3 genomes AF: 0.0000608 AC: 8 AN: 131646 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000742

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000243

Gnomad SAS AF: 0.000257

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000820

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00993 AC: 103 AN: 10368 Hom.: 0 AF XY: 0.00914 AC XY: 70 AN XY: 7660

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00746

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.00508

Gnomad4 SAS exome AF: 0.00512

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.0000608 AC: 8 AN: 131670 Hom.: 0 Cov.: 20 AF XY: 0.0000471 AC XY: 3 AN XY: 63670

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000741

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000244

Gnomad4 SAS AF: 0.000257

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000820

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

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHANK3: BS2 -

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;