11-71118812-T-C

Variant names:

• chr11-71118812-T-C
• rs3924047
• NM_012309.5:c.411+17A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012309.5(SHANK2):​c.411+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,531,148 control chromosomes in the GnomAD database, including 192,460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.49 (18712 hom., cov: 33)
  • Exomes 𝑓: 0.50 (173748 hom.)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83
• 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, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 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.411+17A>G		intron	N/A	NP_036441.2	Q9UPX8-3
	SHANK2	NM_001441024.1		c.411+17A>G		intron	N/A	NP_001427953.1
	SHANK2	NM_001441025.1		c.411+17A>G		intron	N/A	NP_001427954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.411+17A>G		intron	N/A	ENSP00000469689.2	Q9UPX8-3
	SHANK2	ENST00000916035.1		c.411+17A>G		intron	N/A	ENSP00000586094.1
	SHANK2	ENST00000916037.1		c.411+17A>G		intron	N/A	ENSP00000586096.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75100 AN: 151964 Hom.: 18682 Cov.: 33

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.501 AC: 69466 AN: 138556 AF XY: 0.493

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.523

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.500 AC: 689248 AN: 1379066 Hom.: 173748 Cov.: 32 AF XY: 0.496 AC XY: 335984 AN XY: 677428

African (AFR) AF: 0.482 AC: 15136 AN: 31390

American (AMR) AF: 0.556 AC: 19339 AN: 34800

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 9880 AN: 23628

East Asian (EAS) AF: 0.637 AC: 22659 AN: 35580

South Asian (SAS) AF: 0.427 AC: 31853 AN: 74590

European-Finnish (FIN) AF: 0.527 AC: 25443 AN: 48284

Middle Eastern (MID) AF: 0.435 AC: 2444 AN: 5618

European-Non Finnish (NFE) AF: 0.500 AC: 534129 AN: 1067916

Other (OTH) AF: 0.495 AC: 28365 AN: 57260

GnomAD4 genome AF: 0.494 AC: 75194 AN: 152082 Hom.: 18712 Cov.: 33 AF XY: 0.497 AC XY: 36946 AN XY: 74348

African (AFR) AF: 0.479 AC: 19876 AN: 41490

American (AMR) AF: 0.534 AC: 8165 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3470

East Asian (EAS) AF: 0.601 AC: 3103 AN: 5160

South Asian (SAS) AF: 0.422 AC: 2034 AN: 4816

European-Finnish (FIN) AF: 0.535 AC: 5657 AN: 10578

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33313 AN: 67960

Other (OTH) AF: 0.460 AC: 971 AN: 2112

Alfa AF: 0.516 Hom.: 7420

Bravo AF: 0.495

Asia WGS AF: 0.508 AC: 1767 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.93
DANN	Benign	0.35
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3924047; hg19: chr11-70829858;