chr11-70819416-G-A

Variant names:

• chr11-70819416-G-A
• rs3017493
• NM_012309.5:c.1493+948C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012309.5(SHANK2):​c.1493+948C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,302 control chromosomes in the GnomAD database, including 60,717 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (60717 hom., cov: 36)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.717
• Publications: 6 publications found

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]

SHANK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autism, susceptibility to, 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.1493+948C>T		intron_variant	Intron 12 of 25	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.1493+948C>T		intron_variant	Intron 12 of 25	5	NM_012309.5	ENSP00000469689.2

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135767 AN: 152184 Hom.: 60680 Cov.: 36

Gnomad AFR AF: 0.884

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.854

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.878

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.892 AC: 135865 AN: 152302 Hom.: 60717 Cov.: 36 AF XY: 0.887 AC XY: 66060 AN XY: 74468

African (AFR) AF: 0.884 AC: 36743 AN: 41574

American (AMR) AF: 0.914 AC: 13975 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2651 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4857 AN: 5178

South Asian (SAS) AF: 0.855 AC: 4127 AN: 4828

European-Finnish (FIN) AF: 0.826 AC: 8761 AN: 10604

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61775 AN: 68030

Other (OTH) AF: 0.879 AC: 1859 AN: 2114

Alfa AF: 0.899 Hom.: 106824

Bravo AF: 0.900

Asia WGS AF: 0.872 AC: 3031 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.089
DANN	Benign	0.51
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3017493; hg19: chr11-70665521;