11-70660101-G-C

Variant names:

• chr11-70660101-G-C
• rs525304
• NM_012309.5:c.1937-149C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000601538.6(SHANK2):​c.1937-149C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHANK2 ENST00000601538.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000601538.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	NM_012309.5	MANE Select	c.1937-149C>G		intron	N/A	NP_036441.2
	SHANK2	NM_001441024.1		c.2108-149C>G		intron	N/A	NP_001427953.1
	SHANK2	NM_001441025.1		c.1937-149C>G		intron	N/A	NP_001427954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.1937-149C>G		intron	N/A	ENSP00000469689.2
	SHANK2	ENST00000409161.5	TSL:1	c.170-149C>G		intron	N/A	ENSP00000386491.1
	SHANK2	ENST00000449116.6	TSL:1	n.246-149C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000132 AC: 1 AN: 759268 Hom.: 0 AF XY: 0.00000253 AC XY: 1 AN XY: 395786

African (AFR) AF: 0.00 AC: 0 AN: 20064

American (AMR) AF: 0.00 AC: 0 AN: 34370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20078

East Asian (EAS) AF: 0.00 AC: 0 AN: 33048

South Asian (SAS) AF: 0.0000156 AC: 1 AN: 64076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2998

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 508180

Other (OTH) AF: 0.00 AC: 0 AN: 36966

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.35
PhyloP100		0.0070

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: rs525304; hg19: chr11-70506206;