rs55678639

Variant names:

• chr11-70470286-A-G
• rs55678639
• NM_012309.5:c.*2583T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012309.5(SHANK2):​c.*2583T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,310 control chromosomes in the GnomAD database, including 6,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6308 hom., cov: 33)
  • Exomes 𝑓: 0.34 (4 hom.)
• Consequence: SHANK2 NM_012309.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.266
• Publications: 11 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, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-70470286-A-G is Benign according to our data. Variant chr11-70470286-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 305889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

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.*2583T>C		3_prime_UTR	Exon 26 of 26	NP_036441.2	Q9UPX8-3
	SHANK2	NM_001441024.1		c.*2583T>C		3_prime_UTR	Exon 24 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.*2583T>C		3_prime_UTR	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.*2583T>C		3_prime_UTR	Exon 26 of 26	ENSP00000469689.2	Q9UPX8-3
	SHANK2	ENST00000409161.5	TSL:1	c.*2583T>C		3_prime_UTR	Exon 10 of 10	ENSP00000386491.1	E7EUA2
	SHANK2	ENST00000916035.1		c.*2583T>C		3_prime_UTR	Exon 23 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41491 AN: 152124 Hom.: 6302 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.338 AC: 23 AN: 68 Hom.: 4 Cov.: 0 AF XY: 0.316 AC XY: 12 AN XY: 38

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.355 AC: 22 AN: 62

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.273 AC: 41494 AN: 152242 Hom.: 6308 Cov.: 33 AF XY: 0.272 AC XY: 20235 AN XY: 74446

African (AFR) AF: 0.138 AC: 5727 AN: 41550

American (AMR) AF: 0.335 AC: 5129 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1007 AN: 3470

East Asian (EAS) AF: 0.178 AC: 921 AN: 5186

South Asian (SAS) AF: 0.225 AC: 1088 AN: 4832

European-Finnish (FIN) AF: 0.361 AC: 3831 AN: 10598

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22957 AN: 67986

Other (OTH) AF: 0.293 AC: 620 AN: 2116

Alfa AF: 0.298 Hom.: 1617

Bravo AF: 0.269

Asia WGS AF: 0.182 AC: 637 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autism spectrum disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.32
DANN	Benign	0.47
PhyloP100		-0.27
Mutation Taster		=100/0	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: rs55678639; hg19: chr11-70316391;