rs543988574

Variant names:

• chr11-70485471-C-T
• rs543988574
• NM_012309.5:c.4822G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012309.5(SHANK2):​c.4822G>A​(p.Val1608Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: SHANK2 NM_012309.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.233
• Publications: 5 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02334249).
• BP6: Variant 11-70485471-C-T is Benign according to our data. Variant chr11-70485471-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 436712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 20 AD gene.

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.4822G>A	p.Val1608Ile	missense	Exon 25 of 26	NP_036441.2	Q9UPX8-3
	SHANK2	NM_001441024.1		c.4942G>A	p.Val1648Ile	missense	Exon 23 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.4771G>A	p.Val1591Ile	missense	Exon 22 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.4822G>A	p.Val1608Ile	missense	Exon 25 of 26	ENSP00000469689.2	Q9UPX8-3
	SHANK2	ENST00000409161.5	TSL:1	c.3034G>A	p.Val1012Ile	missense	Exon 9 of 10	ENSP00000386491.1	E7EUA2
	SHANK2	ENST00000916035.1		c.4771G>A	p.Val1591Ile	missense	Exon 22 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251316 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461612 Hom.: 0 Cov.: 33 AF XY: 0.000254 AC XY: 185 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000301 AC: 335 AN: 1112010

Other (OTH) AF: 0.000315 AC: 19 AN: 60392

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74470

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autism, susceptibility to, 17 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.1
DANN	Benign	0.78
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.23
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.034
Sift	Benign	0.38	T
Sift4G	Benign	0.40	T
Polyphen		0.11	B
Vest4		0.098
MVP		0.25
MPC		0.44
ClinPred		0.015	T
GERP RS		0.15
gMVP		0.18
Mutation Taster		=94/6	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: rs543988574; hg19: chr11-70331576; COSMIC: COSV53588375; COSMIC: COSV53588375;