11-70473268-C-A

Variant names:

• chr11-70473268-C-A
• NM_012309.5:c.5151G>T
• SHANK2 p.Met1717Ile

Variant summary

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

The NM_012309.5(SHANK2):​c.5151G>T​(p.Met1717Ile) variant causes a missense 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. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SHANK2 NM_012309.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• 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, PanelApp Australia

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 (MetaRNN=0.031713963).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	NM_012309.5	MANE Select	c.5151G>T	p.Met1717Ile	missense	Exon 26 of 26	NP_036441.2	Q9UPX8-3
	SHANK2	NM_001441024.1		c.5271G>T	p.Met1757Ile	missense	Exon 24 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.5100G>T	p.Met1700Ile	missense	Exon 23 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.5151G>T	p.Met1717Ile	missense	Exon 26 of 26	ENSP00000469689.2	Q9UPX8-3
	SHANK2	ENST00000409161.5	TSL:1	c.3363G>T	p.Met1121Ile	missense	Exon 10 of 10	ENSP00000386491.1	E7EUA2
	SHANK2	ENST00000916035.1		c.5100G>T	p.Met1700Ile	missense	Exon 23 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.94
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.43
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.089
Sift	Benign	0.42	T
Sift4G	Benign	0.48	T
gMVP		0.11
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-70319373;