11-70469624-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_012309.5(SHANK2):c.*3245T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 152,646 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 33)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: SHANK2 NM_012309.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1866/152308) while in subpopulation NFE AF= 0.0167 (1135/68032). AF 95% confidence interval is 0.0159. There are 24 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 1866 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK2	NM_012309.5	c.*3245T>C		3_prime_UTR_variant	26/26	ENST00000601538.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK2	ENST00000601538.6	c.*3245T>C		3_prime_UTR_variant	26/26	5	NM_012309.5	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1866 AN: 152190 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0148 AC: 5 AN: 338 Hom.: 0 Cov.: 0 AF XY: 0.0101 AC XY: 2 AN XY: 198

Gnomad4 FIN exome AF: 0.0150

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0123 AC: 1866 AN: 152308 Hom.: 24 Cov.: 33 AF XY: 0.0122 AC XY: 906 AN XY: 74484

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0138 Hom.: 4

Bravo AF: 0.0127

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.5
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs78378706; hg19: chr11-70315729;