11-70487393-T-C

Variant names:

• chr11-70487393-T-C
• rs62622853
• NM_012309.5:c.2900A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001441024.1(SHANK2):​c.3020A>G​(p.Tyr1007Cys) variant causes a missense change. The variant allele was found at a frequency of 0.023 in 1,614,110 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (26 hom., cov: 32)
  • Exomes 𝑓: 0.024 (455 hom.)
• Consequence: SHANK2 NM_001441024.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.61
• Publications: 23 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041798055).
• BP6: Variant 11-70487393-T-C is Benign according to our data. Variant chr11-70487393-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 130303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.017 (2594/152260) while in subpopulation NFE AF = 0.0258 (1755/68008). AF 95% confidence interval is 0.0248. There are 26 homozygotes in GnomAd4. There are 1216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2594 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	NM_012309.5	MANE Select	c.2900A>G	p.Tyr967Cys	missense	Exon 25 of 26	NP_036441.2
	SHANK2	NM_001441024.1		c.3020A>G	p.Tyr1007Cys	missense	Exon 23 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.2849A>G	p.Tyr950Cys	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.2900A>G	p.Tyr967Cys	missense	Exon 25 of 26	ENSP00000469689.2
	SHANK2	ENST00000409161.5	TSL:1	c.1112A>G	p.Tyr371Cys	missense	Exon 9 of 10	ENSP00000386491.1
	SHANK2	ENST00000916035.1		c.2849A>G	p.Tyr950Cys	missense	Exon 22 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2598 AN: 152142 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0175 AC: 4409 AN: 251454 AF XY: 0.0177

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0236 AC: 34461 AN: 1461850 Hom.: 455 Cov.: 34 AF XY: 0.0234 AC XY: 17033 AN XY: 727220

African (AFR) AF: 0.00373 AC: 125 AN: 33480

American (AMR) AF: 0.0148 AC: 660 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 501 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00791 AC: 682 AN: 86258

European-Finnish (FIN) AF: 0.0163 AC: 870 AN: 53382

Middle Eastern (MID) AF: 0.0232 AC: 134 AN: 5768

European-Non Finnish (NFE) AF: 0.0272 AC: 30248 AN: 1112008

Other (OTH) AF: 0.0205 AC: 1240 AN: 60394

GnomAD4 genome AF: 0.0170 AC: 2594 AN: 152260 Hom.: 26 Cov.: 32 AF XY: 0.0163 AC XY: 1216 AN XY: 74466

African (AFR) AF: 0.00525 AC: 218 AN: 41554

American (AMR) AF: 0.0173 AC: 264 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.0186 AC: 197 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1755 AN: 68008

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0228 Hom.: 127

Bravo AF: 0.0174

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00614 AC: 27

ESP6500EA AF: 0.0275 AC: 236

ExAC AF: 0.0178 AC: 2163

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0267

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.88	T
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Benign	0.043	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.52
MPC		1.0
ClinPred		0.015	T
GERP RS		3.7
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.49
Mutation Taster		=98/2	polymorphism (auto)

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: rs62622853; hg19: chr11-70333498; COSMIC: COSV53625094; COSMIC: COSV53625094;