11-70471335-C-CA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_012309.5(SHANK2):c.*1533_*1534insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 398,676 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (1 hom.)
• Consequence: SHANK2 NM_012309.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.143

Genes affected

SHANK2 (HGNC:14295): (SH3 and multiple ankyrin repeat domains 2) This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, and an SH3 domain. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. Alterations in the encoded protein may be associated with susceptibility to autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 11-70471335-C-CA is Benign according to our data. Variant chr11-70471335-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305892.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00195 (296/151950) while in subpopulation AMR AF= 0.00386 (59/15270). AF 95% confidence interval is 0.00308. There are 4 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK2	NM_012309.5	c.*1533_*1534insT		3_prime_UTR_variant	26/26	ENST00000601538.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK2	ENST00000601538.6	c.*1533_*1534insT		3_prime_UTR_variant	26/26	5	NM_012309.5	P1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 294 AN: 151846 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00240

GnomAD4 exome AF: 0.00229 AC: 566 AN: 246726 Hom.: 1 Cov.: 0 AF XY: 0.00226 AC XY: 282 AN XY: 125050

Gnomad4 AFR exome AF: 0.000696

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00195 AC: 296 AN: 151950 Hom.: 4 Cov.: 33 AF XY: 0.00194 AC XY: 144 AN XY: 74224

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.000285

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autism spectrum disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

SHANK2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs575407872; hg19: chr11-70317440;