11-70820660-C-A

Variant names:

• chr11-70820660-C-A
• rs11237599
• NM_012309.5:c.1197G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001441024.1(SHANK2):​c.1368G>T​(p.Ala456Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 544,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A456A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: SHANK2 NM_001441024.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 9 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441024.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	NM_012309.5	MANE Select	c.1197G>T	p.Ala399Ala	synonymous	Exon 12 of 26	NP_036441.2
	SHANK2	NM_001441024.1		c.1368G>T	p.Ala456Ala	synonymous	Exon 13 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.1197G>T	p.Ala399Ala	synonymous	Exon 12 of 23	NP_001427954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.1197G>T	p.Ala399Ala	synonymous	Exon 12 of 26	ENSP00000469689.2
	SHANK2	ENST00000916035.1		c.1197G>T	p.Ala399Ala	synonymous	Exon 12 of 23	ENSP00000586094.1
	SHANK2	ENST00000916037.1		c.1197G>T	p.Ala399Ala	synonymous	Exon 12 of 23	ENSP00000586096.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000760 AC: 1 AN: 131582 AF XY: 0.0000142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000206

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000367 AC: 2 AN: 544654 Hom.: 0 Cov.: 0 AF XY: 0.00000684 AC XY: 2 AN XY: 292452

African (AFR) AF: 0.00 AC: 0 AN: 15186

American (AMR) AF: 0.00 AC: 0 AN: 32982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18840

East Asian (EAS) AF: 0.00 AC: 0 AN: 31762

South Asian (SAS) AF: 0.00 AC: 0 AN: 60306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00000652 AC: 2 AN: 306598

Other (OTH) AF: 0.00 AC: 0 AN: 29746

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	1.3
DANN	Benign	0.89
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11237599; hg19: chr11-70666765;