11-70468767-G-C

Variant names:

• chr11-70468767-G-C
• rs61885874
• NM_012309.5:c.*4102C>G

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.*4102C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 152,256 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (149 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHANK2 NM_012309.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.635
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-70468767-G-C is Benign according to our data. Variant chr11-70468767-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 305882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.*4102C>G		3_prime_UTR_variant	Exon 26 of 26	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.*4102C>G		3_prime_UTR_variant	Exon 26 of 26	5	NM_012309.5	ENSP00000469689.2
SHANK2	ENST00000409161.5	c.*4102C>G		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000386491.1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5432 AN: 152138 Hom.: 149 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0264

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0370

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16

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: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0357 AC: 5434 AN: 152256 Hom.: 149 Cov.: 33 AF XY: 0.0333 AC XY: 2480 AN XY: 74436

African (AFR) AF: 0.0102 AC: 422 AN: 41538

American (AMR) AF: 0.0331 AC: 506 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4820

European-Finnish (FIN) AF: 0.0264 AC: 280 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0564 AC: 3836 AN: 68024

Other (OTH) AF: 0.0366 AC: 77 AN: 2104

Alfa AF: 0.0168 Hom.: 6

Bravo AF: 0.0362

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autism spectrum disorder Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.9
DANN	Benign	0.67
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61885874; hg19: chr11-70314872;