11-70471272-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012309.5(SHANK2):c.*1597T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 398,978 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 33)
  • Exomes 𝑓: 0.012 (92 hom.)
• Consequence: SHANK2 NM_012309.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-70471272-A-C is Benign according to our data. Variant chr11-70471272-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 305890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK2	NM_012309.5	c.*1597T>G		3_prime_UTR_variant	26/26	ENST00000601538.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK2	ENST00000601538.6	c.*1597T>G		3_prime_UTR_variant	26/26	5	NM_012309.5	P1

Frequencies

GnomAD3 genomes AF: 0.00815 AC: 1240 AN: 152132 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00775

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.0120 AC: 2973 AN: 246728 Hom.: 92 Cov.: 0 AF XY: 0.0117 AC XY: 1458 AN XY: 125054

Gnomad4 AFR exome AF: 0.00585

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.0773

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.00894

Gnomad4 NFE exome AF: 0.00410

Gnomad4 OTH exome AF: 0.00824

GnomAD4 genome AF: 0.00816 AC: 1242 AN: 152250 Hom.: 14 Cov.: 33 AF XY: 0.00913 AC XY: 680 AN XY: 74444

Gnomad4 AFR AF: 0.00611

Gnomad4 AMR AF: 0.0149

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.0629

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00775

Gnomad4 NFE AF: 0.00415

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.0101

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.9
Dann	Benign	0.66

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: rs2154625; hg19: chr11-70317377;