NM_012309.5:c.4991T>C

Variant names:

• chr11-70473428-A-G
• rs150857128
• NM_012309.5:c.4991T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012309.5(SHANK2):​c.4991T>C​(p.Ile1664Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,603,872 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1664I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: SHANK2 NM_012309.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.62
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004924059).
• BP6: Variant 11-70473428-A-G is Benign according to our data. Variant chr11-70473428-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00364 (554/152200) while in subpopulation NFE AF = 0.00544 (370/68006). AF 95% confidence interval is 0.00498. There are 1 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 554 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.4991T>C	p.Ile1664Thr	missense	Exon 26 of 26	NP_036441.2	Q9UPX8-3
	SHANK2	NM_001441024.1		c.5111T>C	p.Ile1704Thr	missense	Exon 24 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.4940T>C	p.Ile1647Thr	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.4991T>C	p.Ile1664Thr	missense	Exon 26 of 26	ENSP00000469689.2	Q9UPX8-3
	SHANK2	ENST00000409161.5	TSL:1	c.3203T>C	p.Ile1068Thr	missense	Exon 10 of 10	ENSP00000386491.1	E7EUA2
	SHANK2	ENST00000916035.1		c.4940T>C	p.Ile1647Thr	missense	Exon 23 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152082 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00394 AC: 951 AN: 241270 AF XY: 0.00422

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00976

Gnomad NFE exome AF: 0.00588

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00470 AC: 6825 AN: 1451672 Hom.: 22 Cov.: 32 AF XY: 0.00477 AC XY: 3445 AN XY: 722488

African (AFR) AF: 0.000807 AC: 27 AN: 33474

American (AMR) AF: 0.00166 AC: 74 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00228 AC: 197 AN: 86248

European-Finnish (FIN) AF: 0.00947 AC: 411 AN: 43416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00531 AC: 5907 AN: 1111896

Other (OTH) AF: 0.00338 AC: 204 AN: 60332

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152200 Hom.: 1 Cov.: 32 AF XY: 0.00375 AC XY: 279 AN XY: 74410

African (AFR) AF: 0.000723 AC: 30 AN: 41504

American (AMR) AF: 0.00170 AC: 26 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.00970 AC: 103 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00477 Hom.: 7

Bravo AF: 0.00290

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00434 AC: 527

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.74
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.23
Sift	Benign	0.40	T
Sift4G	Benign	0.77	T
Polyphen		0.0020	B
Vest4		0.17
MVP		0.39
MPC		0.59
ClinPred		0.013	T
GERP RS		4.8
gMVP		0.18
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs150857128; hg19: chr11-70319533; COSMIC: COSV107311425; COSMIC: COSV107311425;