11-70486110-G-A

Variant names:

• chr11-70486110-G-A
• rs562626379
• NM_012309.5:c.4183C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_012309.5(SHANK2):​c.4183C>T​(p.Pro1395Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHANK2 NM_012309.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.37
• Publications: 3 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
• BP6: Variant 11-70486110-G-A is Benign according to our data. Variant chr11-70486110-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 212165.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012309.5. 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.4183C>T	p.Pro1395Ser	missense	Exon 25 of 26	NP_036441.2
	SHANK2	NM_001441024.1		c.4303C>T	p.Pro1435Ser	missense	Exon 23 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.4132C>T	p.Pro1378Ser	missense	Exon 22 of 23	NP_001427954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.4183C>T	p.Pro1395Ser	missense	Exon 25 of 26	ENSP00000469689.2
	SHANK2	ENST00000409161.5	TSL:1	c.2395C>T	p.Pro799Ser	missense	Exon 9 of 10	ENSP00000386491.1
	SHANK2	ENST00000656230.1		c.3046C>T	p.Pro1016Ser	missense	Exon 15 of 16	ENSP00000499561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.30	T
PhyloP100		7.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.35
MPC		1.0
ClinPred		0.77	D
GERP RS		5.7
gMVP		0.55
Mutation Taster		=52/48	polymorphism

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: rs562626379; hg19: chr11-70332215;