rs141276059

chr11-70485536-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012309.5(SHANK2):c.4757C>T(p.Pro1586Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,612,818 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: SHANK2 NM_012309.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020084053).
• BP6: Variant 11-70485536-G-A is Benign according to our data. Variant chr11-70485536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000486 (74/152290) while in subpopulation SAS AF= 0.00104 (5/4824). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK2	NM_012309.5	c.4757C>T	p.Pro1586Leu	missense_variant	25/26	ENST00000601538.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK2	ENST00000601538.6	c.4757C>T	p.Pro1586Leu	missense_variant	25/26	5	NM_012309.5	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000754 AC: 186 AN: 246804 Hom.: 1 AF XY: 0.000816 AC XY: 110 AN XY: 134824

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.000949

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000839

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1460528 Hom.: 1 Cov.: 33 AF XY: 0.000556 AC XY: 404 AN XY: 726540

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.0000767

Gnomad4 NFE exome AF: 0.000469

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74470

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000767 Hom.: 0

Bravo AF: 0.000578

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000583 AC: 5

ExAC AF: 0.000834 AC: 101

EpiCase AF: 0.00158

EpiControl AF: 0.00124

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 18, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

SHANK2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T;T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
REVEL	Benign	0.24
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		1.0	.;.;.;.;D
Vest4		0.71
MVP		0.41
MPC		1.1
ClinPred		0.047	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs141276059; hg19: chr11-70331641; COSMIC: COSV99577173; COSMIC: COSV99577173;