NM_012309.5:c.*1597T>G

Variant names:

• chr11-70471272-A-C
• rs2154625
• NM_012309.5:c.*1597T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012309.5(SHANK2):​c.*1597T>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 0.0106 in 398,978 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 33)
  • Exomes 𝑓: 0.012 (92 hom.)
• Consequence: SHANK2 NM_012309.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35
• Publications: 0 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 (BayesDel_noAF=-0.89).
• BP6: Variant 11-70471272-A-C is Benign according to our data. Variant chr11-70471272-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 305890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.*1597T>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.*1597T>G		3_prime_UTR_variant	Exon 26 of 26	5	NM_012309.5	ENSP00000469689.2

Frequencies

GnomAD3 genomes AF: 0.00815 AC: 1240 AN: 152132 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00775

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.0120 AC: 2973 AN: 246728 Hom.: 92 Cov.: 0 AF XY: 0.0117 AC XY: 1458 AN XY: 125054

African (AFR) AF: 0.00585 AC: 42 AN: 7180

American (AMR) AF: 0.0160 AC: 119 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 53 AN: 9240

East Asian (EAS) AF: 0.0773 AC: 1769 AN: 22892

South Asian (SAS) AF: 0.00198 AC: 6 AN: 3032

European-Finnish (FIN) AF: 0.00894 AC: 190 AN: 21246

Middle Eastern (MID) AF: 0.00850 AC: 11 AN: 1294

European-Non Finnish (NFE) AF: 0.00410 AC: 648 AN: 158038

Other (OTH) AF: 0.00824 AC: 135 AN: 16374

GnomAD4 genome AF: 0.00816 AC: 1242 AN: 152250 Hom.: 14 Cov.: 33 AF XY: 0.00913 AC XY: 680 AN XY: 74444

African (AFR) AF: 0.00611 AC: 254 AN: 41564

American (AMR) AF: 0.0149 AC: 228 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.0629 AC: 326 AN: 5184

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4824

European-Finnish (FIN) AF: 0.00775 AC: 82 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 68000

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.0101

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.89
CADD	Benign	2.9
DANN	Benign	0.66
PhyloP100		1.4
Mutation Taster		=100/0	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: rs2154625; hg19: chr11-70317377;