22-50674428-G-GCGC

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_39dup(p.Ala13dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 20)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 inframe_insertion
• Clinical Significance: 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001372044.2
• BP6: Variant 22-50674428-G-GCGC is Benign according to our data. Variant chr22-50674428-G-GCGC is described in ClinVar as [Benign]. Clinvar id is 3026192.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00301 (396/131666) while in subpopulation AFR AF= 0.00904 (324/35828). AF 95% confidence interval is 0.00823. There are 6 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd at 395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK3	NM_001372044.2	c.37_39dup	p.Ala13dup	inframe_insertion	2/25	ENST00000710353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK3	ENST00000692848.1	c.-191_-189dup		5_prime_UTR_variant	1/10
SHANK3	ENST00000414786.7	n.37_39dup		non_coding_transcript_exon_variant	1/23	5
SHANK3	ENST00000673971.2	c.-191_-189dup		5_prime_UTR_variant, NMD_transcript_variant	1/23

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 395 AN: 131642 Hom.: 6 Cov.: 20

Gnomad AFR AF: 0.00903

Gnomad AMI AF: 0.0288

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000486

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000443

Gnomad OTH AF: 0.00221

GnomAD4 exome AF: 0.000360 AC: 4 AN: 11126 Hom.: 0 Cov.: 0 AF XY: 0.000243 AC XY: 2 AN XY: 8220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00231

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000340

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00301 AC: 396 AN: 131666 Hom.: 6 Cov.: 20 AF XY: 0.00300 AC XY: 191 AN XY: 63670

Gnomad4 AFR AF: 0.00904

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000488

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000273

Gnomad4 NFE AF: 0.000443

Gnomad4 OTH AF: 0.00219

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

SHANK3: BS1, 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;